Process for synthesis of heteroaryl-substituted urea compounds useful as antiinflammatory agents

A process of producing an intermediate compound of formula (IV):

• 22
• comprising:
• reducing compound of formula (III) by catalytic hydrogenation with a Pd/C catalyst under about 30 psi for about 1-24 hours:
• 23
• wherein:
• Z is a nitro or nitroso group;
• Ar2 is phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl or indole each being optionally substituted with one to three R2 groups;
• R2 is selected from the group consisting of:
• a C1-6 branched or unbranched alkyl optionally partially or fully halogenated, acetyl, aroyl, C1-4 branched or unbranched alkoxy optionally partially or fully halogenated, halogen, methoxycarbonyl and phenylsulfonyl;
• L, a linking group, is:
• C1-10 saturated or unsaturated branched or unbranched carbon chain;
• wherein one or more methylene groups are optionally independently replaced by O, NH or S;
• and
• wherein said linking group is optionally substituted with oxo and one or more C1-4 branched or unbranched alkyl optionally substituted by one or more halogen atoms;
• or L is a cyclic group which is:
• a) a C5-8 cycloalkyl or cycloalkenyl optionally substituted with 1-2 oxo groups, 1-3 C1-4 branched or unbranched alkyl, C1-4 alkoxy or C1-4 alkylamino chains;
• b) phenyl, furan, thiophene, pyrrole, imidazolyl, pyridine, pyrimidine, pyridinone, dihydropyridinone, maleimide, dihydromaleimide, piperdine, piperazine or pyrazine each being optionally independently substituted with 1-3 C1-4 branched or unbranched alkyl, C1-4alkoxy, hydroxy, cyano, mono- or di-(C1-3 alkyl)amino, C1-6 alkyl-S(O)q, or halogen;
• wherein said cyclic group is optionally attached to a C1-4 saturated or unsaturated branched or unbranched carbon chain wherein said carbon chain is in turn covalently attached to Q, said carbon chain is optionally partially or fully halogenated and wherein one or more methylene groups are optionally replaced by O, NH, S(O), S(O)2 or S, wherein said methylene groups are further optionally independently substituted with oxo and one or more C1-4 branched or unbranched alkyl optionally substituted by one or more halogen atoms;
• Q is selected from the group consisting of:
• a) phenyl, naphthyl, pyridine, pyrimidine, pyridazine, imidazole, benzimidazole, furan, thiophene, pyran, naphthyridine, oxazo[4,5-b]pyridine and imidazo[4,5-b]pyridine, which are optionally substituted with one to three groups selected from the group consisting of halogen, C1-6 alkyl, C1-6 alkoxy, hydroxy, mono- or di-(C1-3 alkyl)amino, C1-6 alkyl-S(O)m and phenylamino wherein the phenyl ring is optionally substituted with one to two groups selected from the group consisting of halogen, C1-6 alkyl and C1-6 alkoxy;
• b) tetrahydropyran, tetrahydrofuran, 1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine sulfoxide, thiomorpholine sulfone, piperidine, piperidinone, tetrahydropyrimidone, cyclohexanone, cyclohexanol, pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxide and tetramethylene sulfone which are optionally substituted with one to three groups selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, hydroxy, mono- or di-(C1-3 alkyl)amino-C1-3 alkyl, phenylamino-C1-3 alkyl and C1-3 alkoxy-C1-3 alkyl;
• c) C1-6 alkoxy, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to groups selected from the group consisting of C1-3 alkyl and C1-5 alkoxyalkyl and phenyl wherein the phenyl ring is optionally substituted with one to two groups selected from the group consisting of halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino, C1-6 alkyl-S(O)r and phenyl-S(O)t, wherein the phenyl ring is optionally substituted with one to two groups consisting of halogen, C1-6 alkoxy, hydroxy and mono- or di-(C1-3 alkyl)amino;
• m is 0, 1 or 2;
• q is 0, 1 or 2;
• r is 0, 1 or 2;
• t is 0, 1 or 2;and
• to produce the intermediate of formula (IV).