Patent ID: 6683191
Filing Date: 2004-01-27
Classification: C07D

Abstract:
A method of synthesizing highly substituted azole compounds of formula (I): whereinX is selected from the group consisting of NH, NRA and S; represents a 5 membered aromatic ring structure optionally containing one to two additional heteroatoms selected horn the group consisting of N, O and S; wherein the additional heteroatoms are not at the attachment point of the R2 group; wherein the 5 membered ring remains aromatic in nature; wherein the 5 membered ring is optionally substituted with one to three substituents independently selected from the group consisting of halogen, hydroxy, alkyl, alkenyl, halogenated alkyl, cycloalkyl, alkoxy, aryl, aralkyl, heterocyclyl, amino, mono- or di-alkyl amino, mono- or di-cycloalkylamino, mono- or di-arylamino, mono- or di-aralkylamino, cyano, nitro, â€”COOR, â€”COR, â€”SO2R end â€”CONRbRC; wherein the cycloalkyl, aryl or heterocyclyl may be further optionally substituted with one or more substituents wherein the one or more substituents are independently selected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono- or di-alkyl amino, cyano or nitro; R2 is Z is selected from the group consisting of hydrogen, â€”OH, â€”OR, â€”NRARB, N(RA)ORB, â€”SR, â€”CN, â€”N3, and wherein represents a three to eight membered heterocyclyl group bound at the N atom, wherein the heterocyclyl group is saturated, partially unsaturated or aromatic; when the heterocyclyl group is a saturated six to eight membered heterocyclyl, the heterocyclyl group may optionally contains a group selected from O, CHR, NR, S, SO, or SO2, provided that that the group is separated from the N atom by at least two carbon atoms; and wherein the heterocyclyl group is optionally substituted with one or more substituents independently selected from R;R3 is hydrogen; R4 is selected from the group consisting of aryl, aralkyl, alkenyl, alkynyl, aralkynyl, and heterocyclyl; wherein the, alkenyl, alkynyl, aryl, aralkyl, aralkynyl, or heterocyclyl may be optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, halogenated alkyl, aryl, alkoxy, aryloxy, amino, mono- or di-alkyl amino, mono- or di-cycloalkylamino, mono- or di-arylamino, mono- or di-aralkylamino, cyano or nitro; where R is selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, fluorinated alkyl and heterocycle; wherein the alkyl, aryl, aralkyl or heterocycle may be optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono- or di-alkyl amino, cyano or nitro; where RA is selected from the group consisting of hydrogen, â€”R, â€”COOR, â€”COR, â€”SO2R and â€”CONRBRC and where RB and RC are independently selected form the group consisting of hydrogen, alkyl, aryl, aralkyl, cycloalkyl, fluorinated alkyl and heterocycle; wherein the aryl, aralkyl or heterocycle may be optionally substituted with one or more substituents independently selected from halogen, hydroxy, alkyl, halogenated alkyl, alkoxy, amino, mono- or di-alkyl amino, mono- or di-cycloalkylamino, mono- or di-arylamino, mono- or di-aralkylamino, cyano or nitro; or are joined together to form a 4 to 8 membered heterocyclyl ring structure; which method comprises: a) preparing a compound of the formula (III) on a solid support resin, â€ƒby reacting a carbonyl chloride substituted resin of formula (VII) with an aromatic heterocycle of formula (VIII) and an aldehyde of formula (IX) â€ƒwherein R3 and R4 are as described above; b) cleaving the compound from the solid support resin by nucleophilic substitution to yield the corresponding compound of formula (I); c) optionally further substituting the compound of formula (I) via alkylation reactions in solution phase.