Process and intermediates for the production of CCR2 antagonists

A process for the production of a compound of formula (I),

• wherein
• R1 is selected from the group consisting of
• R2 is selected from the group consisting of —H, -halogen, —CN, —O—C1-C4-alkyl, —C1-C4-alkyl, —CH═CH2, —C≡CH, —CF3, —OCF3, —OCF2H, and —OCFH2;
• R3 is selected from the group consisting of —H, -methyl, -ethyl, -propyl, -i-propyl, -cyclopropyl, —OCH3, and —CN;
• R4 and R5 are independently selected from the group consisting of an electron pair, —H, —C1-C6-alkyl, —NH2, —C3-C8-cycloalkyl, —C3-C8-heterocyclyl, —C5-C10-aryl, —C5-C10-heteroaryl, and —C(O)—N(R8,R8′), with R8 and R8′ independently being selected from the group consisting of —H, and —C1-C6-alkyl,
• and wherein R4 and R5 if different from an electron pair or —H are optionally independently substituted with one or more groups selected from the group consisting of -halogen, —OH, —CF3, —CN, —C1-C6-alkyl, —O—C1-C6-alkyl, —O—C3-C8-cycloalkyl, —O—C3-C8-heterocyclyl, —O—C5-C10-aryl, —O—C5-C10-heteroaryl, —C0-C6-alkylene-CN, —C0-C4-alkylene-O—C1-C4-alkyl, —C0-C4-alkylene-O—C3-C8-cycloalkyl, —C0-C4-alkylene-O—C3-C8-heterocyclyl, —C0-C4-alkylene-O—C5-C10-aryl, —C0-C4-alkylene-O—C5-C10-heteroaryl, —C0-C4-alkylene-Q-C0-C4-alkyl-N(R9,R9′), —C0-C4-alkylene-N(R10)-Q-C1-C4-alkyl, —C0-C4-alkylene-N(R10)-Q-C3-C8-cycloalkyl, —C0-C4-alkylene-N(R10)-Q-C3-C8-heterocyclyl, —C0-C4-alkylene-N(R10)-Q-C5-C10-aryl, —C0-C4-alkylene-N(R10)-Q-C5-C10-heteroaryl, —C0-C4-alkylene-Q-N(R11,R11′), —C0-C4-alkylen-N(R12)-Q-N(R13,R13′), —C0-C4-alkylen-R14, —C0-C4-alkylene-Q-C1-C6-alkyl, —C0-C4-alkylene-Q-C3-C8-cycloalkyl, —C0-C4-alkylene-Q-C3-C8-heterocyclyl, —C0-C4-alkylene-Q-C5-C10-aryl, —C0-C4-alkylene-Q-C5-C10-heteroaryl, —C0-C4-alkylene-O-Q-N(R15,R15′), and —C0-C4-alkylene-N(R16)-Q-O—(R17),
• wherein Q is —C(O)— or —SO2—,
• wherein R12, R16, are independently selected from the group consisting of —H, —C1-C6-alkyl, and —C3-C6-cycloalkyl,
• wherein R9, R9′, R10, R11, R11′, R13, R13′, R15, R15′, are independently selected from the group consisting of —H, —C1-C6-alkyl, and —C3-C6-cycloalkyl,
• or wherein R9 and R9′, R11 and R11′, R13 and R13′, R15 and R15′ together form a —C2-C6-alkylene group,
• wherein R14 and R17 are independently selected from the group consisting of —H, —C1-C6-alkyl, —C5-C10-aryl, —C5-C10-heteroaryl, —C3-C8-cycloalkyl, and —C3-C8-heterocyclyl, wherein said —C3-C8-heterocyclyl optionally comprises nitrogen and/or —SO2— in the ring,
• and wherein R14 and R17 are optionally substituted with one or more groups selected from the group consisting of —OH, —OCH3, —CF3, —OCF3, —CN, -halogen, —C1-C4-alkyl, ═O, and —SO2—C1-C4-alkyl,
• or R4 and/or R5 are independently a group of the structure -L2-R18,
• wherein L2 is —NH— and/or N(C1-C4-alkyl)-,
• wherein R18 is —C5-C10-aryl, —C5-C10-heteroaryl, —C3-C8-cycloalkyl or —C3-C8-heterocyclyl,
• wherein R18 is optionally substituted by one or more groups selected from the group consisting of halogen, —CF3, —OCF3, —CN, —OH, —O—C1-C4-alkyl, —C1-C6-alkyl, —NH—C(O)—C1-C6-alkyl, —N(C1-C4-alkyl)-C(O)—C1-C6-alkyl, —C(O)—C1-C6-alkyl, —S(O)2—C1-C6-alkyl, —NH—S(O)2—C1-C6-alkyl, —N(C1-C4-alkyl)-S(O)2—C1-C6-alkyl, and —C(O)—O—C1-C6-alkyl;
• R6 is selected from the group consisting of —H, —C1-C4-alkyl, —OH, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3;
• A is —NH—;
• n is 1, 2 or 3;
• Z is C or N,
• characterized in that a compound of formula II
• in which R2, R3, R4, R5, R6, Z, and n have the meaning as in formula I, is coupled with a primary amine selected from the group consisting of