Patent GB-1299295-A (GB)
Title: Improvements in or relating to naphthyl acetic acid esters
IPC: C07C51/487
Filed: 1970-03-10
Abstract: 1299295 Naphthyl acetic acid esters SYNTEX CORP 10 March 1970 [24 March 1969] 11482/70 Heading C2C Novel compounds of the general formulae wherein R is a C 13-22  alkyl, C 3  to C 7  cycloalkyl, C 4  to C 9  cyoloalkyl methyl, C 5  to C 10  2-cycloalkyl-ethyl, 3-cyclo pentyl propyl, 3-cyclo hexylpropyl, benzyl, 2-phenethyl, or 3-phenyl propyl or C 1-12  alkyl in resolved compounds II; one of R 1  and R 2  is hydrogen, the other is methyl or difluoro-methyl or R 1  and R 2  taken together are methylene or difluoromethylene; R 3  is cyclopropyl, trifluoromethyl, vinyl, ethynyl, difluoromethoxy, difluoromethylthic or acetyl or R 4  is methyl, ethyl, isopropyl. cyclopropyl, trifluoromethyl, vinyl, ethynyl, fluoro, chloro, methoxy, methoxymethyloxy, difluoromethoxy, methyl thio, methoxymethyl thio, difluoromethylthio or acetyl are prepared by esterifying the corresponding carboxylic acid optionally via the acid chloride. The starting α-naphyl propionic acid and naphthyl acetic acids may be prepared by Friedel Craft reaction of acetyl chloride with a #-monosubstituted naphthylene derivative to yield a 2 - acetyl - 6 - substituted naphthalene followed by a Willgerodt rearrangement to 2-(6-substituted-2- naphthyl) acetic acid, which may be optionally esterified, reacted with methyl iodide and sodium hydride followed by hydrolysis to yield 2-(6-subtituted-2-naphthyl) propionic acid. The 2 - (6 - substituted - 2 - naphthyl) - 2,2- difluoromethylene acetic acids may be prepared from methyl 2 - (6 - substituted - 2 - naphthyl) acetate by reaction with sodium then ethyl formate to yield methyl 2-(6-substituted-2- naphthyl)-2,2-hydroxy methylene acetate which on treatment with sodium hydride and chlorine yields methyl 2 - (6 - substituted - 2 - naphthyl)- 2 - formyl - 2 - chloroacetate which is oxidised to methyl 2 - (6 - substituted - 2 - naphthyl)- 2-carboxy-2-chloroacetate which is decarboxylated to methyl 2-(6-substituted-2-naphthyl)- 2-chloroacetate followed by hydrolysis of chloro to hydroxyl and oxidation of the hydroxyl to yield methyl 2 - (6 - substituted - 2 - naphthyl)- 2-oxoacetate which on treatment with difluoromethylene triphenylphosphorane yields methyl 2 - (6 - substituted - 2 - naphthyl) - 2,2 - difluoromethylene acetate which may be hydrolysed to the free acid. The 2 - (6 - substituted - 2 - naphthyl) - 2,2- methylene acetic acids may be prepared from methyl 2-(6-substituted-2-naphthyl) acetate by treatment with sodium methoxide and paraformaldehyde to introduce the 2,2-methylene group therein and hydrolysis to the free acid. Methyl 2-(6-substituted-2-naphthyl)-2-hydroxymethylene acetate is formed as a by-product in the first step. The 2 - (6 - substituted - 2 - naphthyl) -2- difluoromethyl acetic acids may be formed from the 2 - (6 - substituted - 2 - naphthyl) acetic acid by formation of the ethyl ester, reaction of the product with diethyl carbonate and sodium hydride to yield diethyl (6-substituted-2- naphthyl) malonate, reaction with chlorodifluoromethane in the presence of strong base to yield diethyl (6-substituted-2-naphthyl)-α- difluoromethyl malonate followed by hydrolysis and decarboxylation to the required product. The substituents in the 6-position of the naphthalene ring may be interchanged, thus (a) methylthio may be demethylated and reacted with chlorodifluoromethane to yield a difluoromethylthio group, (b) methyl may be chlorinated and then fluorinated to form trifluoromethy]. (c) vinyl may be brominated and dehydrobrominated to yield ethynyl, and (d) vinyl may be reacted with formic acid to yield 1-hydroxyethyl which may be oxidized to acetyl. Pharmaceutical compositions of compounds I or II with the usual excipients show antiinflammatory, analgesic and anti-pyretic activity when administered parenterally or orally.