Patent ID: 6639082
Filing Date: 2003-10-28
Classification: A61P,C07D,C07F

Abstract:
A method for the preparation of a biphenyl sulfonamide of the following formula I where the phenyl rings of the biphenyl group may independently be unsubstituted or substituted with one or more substituent groups, enantiomers and diastereomers, and salts thereof, wherein one of X and Y is N and the other is O; R3 and R4 are each directly bonded to a ring carbon and are each independently (a) hydrogen; (b) alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl or aryloxy, any of which may be substituted with Z1, Z2 and Z3; (c) halo; (d) hydroxyl; (e) cyano; (f) nitro; (g) â€”C(O)H or â€”C(O)R5; (h) â€”CO2H or â€”CO2R5; (i) â€”Z4â€”NR6R7; â€”Z4â€”N(R10)â€”Z5â€”NR8R9; or (k) R3 and R4 together may also be alkylene or alkenylene, either of which may be substituted with Z1, Z2 and Z3, completing a 4- to 8-membered saturated, unsaturated or aromatic ring together with the carbon atoms to which they are attached; R5 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3; R6, R7, R8, R9 and R10 are each independently (a) hydrogen; or (b) alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3; or R6 and R7 together may be alkylene or alkenylene, either of which may be substituted with Z1, Z2 and Z3, completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached; or any two of R8, R9 and R10 together are alkylene or alkenylene, either of which may be substituted with Z1, Z2 and Z3, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached; Z1, Z2 and Z3 are each independently (a) hydrogen; (b) halo; (c) hydroxy; (d) alkyl; (e) alkenyl; (f) aryl; (g) aralkyl; (h) alkoxy; (i) aryloxy; (j) aryloxy; (k) heterocycle, substituted heterocycle or heterocyclooxy; (l) â€”SH, â€”S(O)nZ6, â€”S(O)mâ€”OH, â€”S(O)mâ€”OZ6, â€”Oâ€”S(O)mâ€”Z6, â€”Oâ€”S(O)mOH or â€”Oâ€”S(O)mâ€”OZ6; (m) oxo; (n) nitro; (o) cyano; (p) â€”C(O)H or â€”C(O)Z6; (q) â€”CO2H or â€”CO2Z6; (r) â€”Z4â€”NZ7Z8; (s) â€”Z4â€”N(Z11)â€”Z5â€”H; (t) â€”Z4â€”N(Z11)â€”Z5â€”Z6; or (u) â€”Z4â€”N(Z11)â€”Z5â€”NZ7Z8; Z4 and Z5 are each independently (a) a single bond; (b) â€”Z9â€”S(O)nâ€”Z10â€”; (c) â€”Z9â€”C (O)â€”Z10â€”; (d) â€”Z9â€”C(S)â€”Z10â€”; (e) â€”Z9â€”Oâ€”Z10â€”; (f) â€”Z9â€”Sâ€”Z10â€”; (g) â€”Z9â€”Oâ€”C(O)â€”Z10â€”; or (h) â€”Z9â€”C(O)â€”Oâ€”Z10â€”; Z6 is alkyl; alkyl substituted with one to three groups selected from halogen, aryl, aryloxy and alkoxy; alkenyl; alkynyl; cycloalkyl; cycloalkyl substituted with one to three groups selected from alkyl, aryl, alkenyl and alkoxyaryl; cycloalkyl to which is fused a benzene ring; aryloxy substituted with one or two halogens; cycloalkylalkyl; cycloalkenyl; cycloalkenylalkyl; aryl; aryl substituted with methylenedioxy or one to four groups selected from alkyl, dialkylamino, cyano, halogen, trihaloalkyl, alkoxy and trihaloalkoxy; or heterocycle or substituted heterocycle; Z7 and Z8 are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl, or Z7 and Z8 together are alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the nitrogen atom to which they are attached; Z9 and Z10 are each independently a single bond, alkylene, alkenylene or alkynylene; Z11 is (a) hydrogen; or (b) alkyl, alkyl substituted with one, two or three halogens, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl; or any two of Z7, Z8 and Z11 together are alkylene or alkenylene, completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached; each m is independently 1 or 2; and each n is independently 0, 1 or 2; comprising the steps of (a) contacting a pinacol ester of the formula II or salt thereof â€ƒwhere the phenyl ring of said formula II may be further substituted, and where â€œprotâ€  denotes an alkoxymethyl nitrogen-protecting group, with a compound of the formula III or salt thereof â€ƒwhere R16 is halogen or a group â€”Oâ€”Q where Q is â€”SO2CF3, â€”SO2CH3, or â€ƒand where the phenyl ring of said formula III may be further substituted, in the presence of a palladium(0) catalyst and, optionally, a base, to form a compound of the formula IV or salt thereof â€ƒwhere the phenyl rings of the biphenyl group may independently be unsubstituted or substituted with one or more substituent groups; and (b) deprotecting the nitrogen of said compound of the formula IV or salt thereof to form said compound of the formula I or salt thereof.