Process for the synthesis of sulfonyl halides and sulfonamides from sulfonic acid salts

#The present invention relates to processes for the preparation of sulfonyl halides and sulfonamides useful as intermediates in the preparation of, for example, pharmaceuticals and for the preparation of sulfonamides useful as pharmaceuticals.

#Sulfonyl chlorides are widely used in the chemical industry such as for the preparation of dyes, lithographic resists, and pharmaceuticals. They can be further transformed into other functional groups such as aromatic sulfones (by Friedel-Crafts sulfonylation of aromatic substrates) or sulfonamides (by reaction with amines) (see, e.g., Kirk-Othmer Encyclopedia of Chemical Technology). Sulfonamides are integral functional groups of a wide variety of therapeutic small molecule drugs such as antibacterial agents, diuretics, and cPLA2 inhibitors.

#A typical preparation of sulfonyl chlorides involves reaction of the sodium salt of a sulfonic acid with phosphorus pentachloride, sometimes in combination with phosphorus oxychloride or thionyl chloride, frequently with heating of the reaction mixture (see, e.g., March, Advanced Organic Chemistry, 4th ed., John Wiley & Sons, 1992, p. 499). These relatively harsh reaction conditions are unsuitable for the preparation of sterically hindered sulfonyl chlorides, such as arylalkylsulfonyl chlorides and the like, which can result in low yields due to the elimination of sulfur dioxide (Nakayama et al., Tet Lett., 1984, 25, 4553-4556). A milder, infrequently used method for the synthesis of sulfonyl chlorides is the reaction of tetrabutylammonium salts of sulfonic acids with triphenylphosphine/sulfuryl chloride (Widlanski et al., Tet. Lett., 1992, 33, 2657-2660), a method that suffers from the disadvantage of poor atom efficiency.

#The present invention provides a process for the preparation of sulfonyl halides and sulfonamides, such as aryl- and heteroaryl-alkylsulfonyl halides and aryl- and heteroaryl-alkylsulfonamides, including (2-trifluoromethylphenyl)-methanesulfonyl chloride and (2-trifluoromethylphenyl)-methanesulfonamide, which are intermediates in the synthesis of certain cPLA2 inhibitors. In some embodiments, the processes involve the formation of the intermediate sulfonic acid prior to conversion to the sulfonyl halide.

#In some embodiments, the present invention provides a synthetic process that includes reacting a compound of Formula II: [Ar—(R)z—SO3−1]qM  II wherein:

#Ar is C1-C18 alkyl, C2-C18 alkenyl, C2-C18 alkynyl, C3-C18 cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each optionally substituted by up to five substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C3-C7 cycloalkyl, heterocycloalkyl, cyano, nitro, OH, C1-C6 haloalkyl, C1-C3 perhaloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C3 perhaloalkoxy, NR1R2, NR1COR3, COR3, COOR3, OCOR3, aryloxy, heteroaryloxy, arylalkyloxy, heteroarylalkyloxy, cycloalkylalkyl, arylalkyl, heteroarylalkyl, aryl and heteroaryl;