Process for preparing macrocyclic compounds

A compound of the formula (IV):

• wherein R3 is hydroxy, NH2, or a group of formula —NH—R9, wherein R9 is C6 or C10 aryl, heteroaryl, —C(O)—R10, C(O)—NHR10 or —C(O)—OR10,
• wherein R10 is C1-6 alkyl or C3-6 cycloalkyl;
• D is a 3 to 7-atom saturated alkylene chain;
• R4 is H, or from one to three substituents on said chain D with up to two of these substituents possible on any single carbon atom of said chain D, said substituent independently selected from the group consisting of:
• C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, hydroxy, halo, amino, oxo, thio, or C1-6 thioalkyl.

A process for preparing a compound of the following formula (VI):

• wherein:
• R3 is hydroxy, NH2, or a group of formula —NH—R9, wherein R9 is C6 or C10 aryl, heteroaryl, —C(O)—R10, —C(O)—NHR10 or —C(O)—O—C3-6 cycloalkyl,
• wherein R10 is C1-6 alkyl or C3-6 cycloalkyl;
• D is a 3 to 7-atom saturated alkylene chain;
• R4 is H, or from one to three substituents on said chain D with up to two of these substituents possible on any single carbon atom of said chain D, said substituent independently selected from the group consisting of:
• C1-6 alkyl,
• C1-6 haloalkyl, C1-6 alkoxy, hydroxy, halo, amino, oxo, thio, or C1-6 thioalkyl;
• and
• A is an amide of formula —C(O)—NH—R11, wherein R11 is selected from the group consisting of:
• C1-8 alkyl, C3-6 cycloalkyl, C6 or C10 aryl;
• C7-16 aralkyl and SO2R11A wherein R11A is C1-8 alkyl, C3-7 cycloalkyl or C1-6 alkyl-C3-7 cycloalky;
• or A is a carboxylic acid or a pharmaceutically acceptable salt or ester thereof,
• said process comprising reacting a compound of formula (IV) with a compound of formula (V) in the presence of a suitable base in suitable solvent to obtain a compound of formula (VI):
• wherein R3, R4, D and A are as defined in formula (VI) above.

A compound of the formula (VIII):

• wherein:
• R3 is hydroxy, NH2, or a group of formula —NH—R9, wherein R9 is C6 or C10 aryl, heteroaryl, —C(O)—R10, —C(O)—NHR10 or —C(O)—OR10,
• wherein R10 is C1-6 alkyl or C3-6 cycloalkyl;
• D is a 3 to 7-atom saturated alkylene chain;
• R4 is H, or from one to three substituents on said chain D with up to two of these substituents possible on any single carbon atom of said chain D, said substituent independently selected from the group consisting of:
• C1-6 alkyl,
• C1-6 haloalkyl, C1-6 alkoxy, hydroxy, halo, amino, oxo, thio, or C1-6 thioalkyl;
• and
• A is an amide of formula —C(O)—NH—R11, wherein R11 is selected from the group consisting of:
• C1-8 alkyl, C3-6 cycloalkyl, C6 or C10 aryl;
• C7-16 aralkyl and SO2R11A wherein R11A is C1-8 alkyl, C3-7 cycloalkyl or C1-6 alkyl-C3-7 cycloalkyl;
• or A is a carboxylic acid or a pharmaceutically acceptable salt or ester thereof;
• and
• R12 is selected from p-tolyl, p-bromophenyl, p-nitrophenyl, methyl, trifluoromethyl, perfluorobutyl and 2,2,2-trifluoroethyl.

A compound of formula (IX):

• wherein R3 is hydroxy, NH2, or a group of formula —NH—R9, wherein R9 is C6 or C10 aryl, heteroaryl, —C(O)—R10, —C(O)—NHR10 or —C(O)—OR10,
• wherein R10 is C1-6 alkyl or C3-6 cycloalkyl;
• D is a 3 to 7-atom saturated alkylene chain;
• R4 is H, or from one to three substituents on said chain D with up to two of these substituents possible on any single carbon atom of said chain D, said substituent independently selected from the group consisting of:
• C1-6 alkyl,
• C1-6 haloalkyl, C1-6 alkoxy, hydroxy, halo, amino, oxo, thio, or C1-6 thioalkyl;
• and
• A is an amide of formula —C(O)—NH—R11, wherein R11 is selected from the group consisting of:
• C1-8 alkyl, C3-6 cycloalkyl, C6 or C10 aryl;
• C7-16 aralkyl and SO2 R11A wherein R11A is C1-8 alkyl, C3-7 cycloalkyl or C1-6 alkyl-C3-7 cycloalkyl;
• or A is a carboxylic acid or a pharmaceutically acceptable salt or ester thereof;
• and
• R12 is selected from p-tolyl, p-bromophenyl, p-nitrophenyl, methyl, trifluoromethyl, perfluorobutyl and 2,2,2-trifluoroethyl.