Patent ID: 6512120
Filing Date: 2003-01-28
Classification: C07D

Abstract:
A method for generating densely functionalized pyrrolidine intermediates selected from the group consisting of Formula (I) and Formula (II): whereinR1 is selected from the group consisting of a standard, natural (L) and non-natural (D), non-hydrogen amino acid side chain (wherein the amino acid side chain is optionally substituted with a suitable protecting group), hydrogen and â€”(C1-8)alkyl {wherein C1-8alkyl is optionally substituted with 1 to 2 substituents selected from the group consisting of â€”CO2H (wherein CO2H is optionally substituted with a suitable protecting group), -phenyl-R6, -heteroaryl-R6 and hydroxy (wherein hydroxy is optionally substituted with a suitable protecting group)}; alternatively, R1 and R2 may be joined to form a heterocyclyl ring; R6 is one to two substituents selected from the group consisting of hydrogen, â€”(C1-8)alkyl, â€”Oâ€”(C1-8)alkyl, halogen, hydroxy and nitro; R2 is selected from the group consisting of hydrogen (wherein hydrogen is optionally replaced with a suitable protecting group), â€”(C1-8)alkyl, â€”(C1-8)alkyl-Phâ€”R6, â€”C(O)â€”(C1-8)alkyl, â€”C(O)â€”Phâ€”R6, â€”C(O)Oâ€”(C1-8)alkyl, â€”C(O)Oâ€”Phâ€”R6, â€”C(O)Oâ€”(C1-8)alkyl-Phâ€”R6 and â€”SO2â€”Phâ€”R6; R3 is selected from the group consisting of â€”C(O)â€”N(R7R8), â€”CO2H (wherein CO2H is optionally substituted with a suitable protecting group), â€”C(O)â€”Oâ€”(C1-8)alkyl and cyano; R7 is selected from hydrogen, â€”(C1-8)alkyl, â€”(C1-8)alkyl-Phâ€”R6, hydroxy (wherein hydroxy is optionally substituted with a suitable protecting group) or a suitable protecting group; R8 is selected from hydrogen, â€”(C1-8)alkyl, â€”(C1-8)alkyl-Phâ€”R6 or a suitable protecting group; R4 is selected from the group consisting of hydrogen, â€”(C1-8)alkyl and â€”(C1-8)alkyl-Phâ€”R6; R5 is selected from the group consisting of â€”(C1-8)alkyl and â€”Phâ€”R6; Y is optionally present and is selected from the group consisting of O and S; X1 is selected from the group consisting of â€”Oâ€”, â€”N(H)â€”(wherein NH is optionally substituted with a suitable protecting group), â€”N(â€”OH)â€” (wherein hydroxy is optionally substituted with a suitable protecting group), â€”N(â€”Oâ€”(C1-8)alkyl)â€”, â€”N(â€”C1-8alkyl-aryl-R6)â€” and â€”N(â€”Oâ€”(C1-8)alkyl-aryl-R6)â€”; and, X2 is selected from the group consisting of â€”OH (wherein OH is optionally substituted with a suitable protecting group), â€”NH2 (wherein NH2 is optionally substituted with a suitable protecting group), â€”NH(â€”OH) (wherein NH and OH are optionally substituted with a suitable protecting group), â€”NH(â€”C1-8alkyl) (wherein NH is optionally substituted with a suitable protecting group) and â€”NH(â€”C1-8alkyl-aryl-R6) (wherein NH is optionally substituted with a suitable protecting group); and pharmaceutically acceptable salts and diastereomers thereof;wherein the method for generating an intermediate selected from the group consisting of Formula (I) and Formula (II) is either a resin-bound or an in-situ method comprising: (a) preparing a compound of Formula (III): wherein R1 and R4 are as previously described; wherein R9 is selected from R2 (for an in-situ method) or (for a resin-bound method) is selected from â€”SO2â€”Phâ€”CO2â€”(resin) or â€”SO2â€”Phâ€”C(O)â€”NHâ€”(resin); and, wherein R10 is selected from R3 (for an in-situ method) or (for a resin-bound method) is selected from â€”CO2â€”(resin), â€”C(O)â€”NHâ€”(resin) or â€”C(N)â€”(resin); and, (b) acylating the compound of Formula (III) to prepare a compound of Formula (IV): wherein Y, R1, R4, R5, R9 and R10 are as previously described; and, wherein X is selected from the group consisting of O, N(H) (wherein NH is optionally substituted with a suitable protecting group), N(â€”OH) (wherein hydroxy is optionally substituted with a suitable protecting group), N(â€”Oâ€”(C1-8)alkyl), N(â€”C1-8alkyl-aryl-R6) and N(â€”Oâ€”(C1-8)alkyl-aryl-R6); (c) reacting the compound of Formula (IV) (with the proviso that the method is a resin-bound method) with the appropriate starting materials, using the appropriate reagents and conditions and cleaving the compound of Formula (IV) (with the proviso that the method is a resin-bound method) from the resin to prepare the intermediate selected from the group consisting of Formula (I) and Formula (II); or, (d) refluxing the compound of Formula (IV) (with the proviso that the method is an in-situ method) using the appropriate reagents and conditions to prepare the intermediate selected from the group consisting of Formula (I) and Formula (II); wherein the intermediate is selected from a kinetic product (a trans isomer prepared at a reflux temperature of &lE;80Â° C.) or a thermodynamic product (a cis isomer prepared at a reflux temperature of >80Â° C.); alternatively, the method for preparing an intermediate of Formula (I) further comprises preparing a compound selected from Formula (IV) wherein X is NH(â€”OH); and, adding silica gel in the appropriate amount at the appropriate time and temperature to prepare the intermediate of Formula (I) by cycloaddition; and, alternatively, the method for preparing an intermediate of Formula (II) further comprises hydrolyzing an intermediate of Formula (I) under the appropriate conditions to prepare the intermediate of Formula (II).