Process for the synthesis of C-2, C-3 substituted N-alkylated indoles useful as cPLA2 inhibitors

#This invention relates to a process for making substituted indoles useful as cPLA2 inhibitors and intermediate compounds in that process.

#Processes for alkylating the C-3 position of indoles are well known in the art. The effect of different metal cations, base concentration, and catalysts for the phase transfer alkylation of indoles under basic conditions has been studied. Alkylation of indoles can also proceed with catalytic amounts of acid. Trifluoroacetic acid and triethylsilane have been used in combination to simultaneously alkylate and reduce at the C-3 position of indoles. However, trifluoroacetic acid is incompatible with some acid sensitive functional groups, such as benzhydryl groups.

#Known methods for producing N-alkylated indoles generally require expensive materials and processing. An efficient and economical method for producing N-alkylated indoles is therefore desirable.

#The coupling reaction of a compound of formula 3, above, with N-substituted 2-iodo, 4-chloro anilines requires different reaction conditions depending on the identity of the aniline amino substituent. When the amino substituent is a trifluoroacetyl group, for example, the reaction is facile with relatively low levels of catalysts (e.g., about 1 mole % Pd catalyst and 2 mole % CuI) at moderate temperatures (e.g., less than 50° C.). However, when the amino substituent is a benzhydryl group, more Pd catalyst (e.g., about 5 mole % or more) is necessary, which increases the cost and complexity of the synthesis and purification.

#It has been discovered that the coupling reaction of compounds of formulas 2 and 3 will proceed efficiently to produce the compound of formula 4 in high yield when the amount of palladium catalyst is reduced (e.g., about 0.5 mole % to about 1.5 mole %), provided that the copper catalyst is present in at least about 5 mole % and at least about 2 equivalents (i.e., about 200 mole %) of a base is used. The use of less palladium catalyst makes the method of the invention more efficient and economical.

#The present invention provides method for making a compound of formula 1: