Patent GB-1364516-A (GB)
Title: Fluorene - 2 - acetic acids and derivatives process and method of using
IPC: C07C57/50
Filed: 1971-08-19
Abstract: 1364516 Fluorene - 2 - acetic acids and derivatives E R SQUIBB & SONS Inc 19 Aug 1971 [9 Sept 1970] 39052/71 Heading C2C Novel compounds of the general Formula I wherein X is hydrogen, C 1 -C 8  alkyl or alkoxy, hydroxyl halogen, amino, trifluoromethyl or nitro and Y is wherein Z is COOH, COOR<SP>5</SP> or CN; R<SP>1</SP> is hydrogen, hydroxy, C 1 -C 8  alkyl or C 3 -C 6  cycloalkyl or (C 3 -C 6  cycloalkyl)-alkyl; R<SP>2</SP> is hydrogen, C 1 -C 12  alkyl or C 3 -C 6  cycloalkyl or (C 3 -C 6 -cycloalkyl)-alkyl; R<SP>3</SP> is hydrogen or C 1 -C 8  alkyl; R<SP>4</SP> is hydrogen, C 1 -C 8  alkyl, or C 3 -C 6  cycloalkyl or (C 3 -C 6 -cycloalkyl)-alkyl; and R 5  is hydrogen, C 1 -C 8  alkyl, aryl, aralkyl, or a metallic ion with the proviso that when Y is CH 2 COOH or salts thereof X may not be hydrogen, chlorine, nitro or amino, may be prepared (a) by Friedel Craft reaction of a mono acid halide of a oxalyl ester with fluorene or a 7-substituted fluorene to yield I when Y is CO.COOR<SP>3</SP> optionally followed by hydrolysis, (b) reacting products of (a) with an R<SP>4</SP> methylene-triphenylphosphonium halide to form a product wherein Y is wherein R<SP>3</SP> and R<SP>4</SP> are as defined above; (c) hydrogenating the product of (b) to saturate the olefinic bond in Y and optionally alkylating the product to introduce R<SP>1</SP> or R<SP>2</SP>; (d) reducing the product of (a) wherein X is other than hydrogen, amino, nitro or halogen (except F and Br) followed by treatment with base to form a compound in which Y is CH 2 COOH; (e) reacting the product of (a) in which R<SP>3</SP> is hydrogen with a Grignard reagent to yield a product in which Y is an α-R<SP>2</SP>, α-hydroxy acetic acid group; (f) for compounds in which X is as in (d) above, reacting a 2-fluorene carboxylic halide with a diazoalkane to form a diazoketone followed by rearrangement and hydrolysis to yield a compound in which Y is an α-alkyl substituted acetic acid group; (g) for compounds in which Y is in which Z is CN or COOH, alkylating a compound in which R<SP>2</SP> is hydrogen and Z is CN followed optionally by hydrolysis of the cyano group; (h) for compounds in which Y is or forming a cyanohydrin of a 2-fluorene-R<SP>2</SP>- ketone optionally followed by dehydration of the hydroxyl group when R<SP>2</SP> has a CH 2  group vicinal to the hydroxyl group, and optionally catalytically hydrogenating the olefinic bond and hydrolysing the product to form the free carboxylic acid; (i) for compounds in which Y is Z is carboxylic acid, R<SP>1</SP> is hydrogen, hydroxyl, alkyl or monocyclic cycloalkyl and R<SP>2</SP> is hydrogen, alkyl or monocyclic cycloalkyl and X is hydroxy by subjecting the corresponding compound in which X is hydrogen to the action of 7-hydroxylating enzymes; (j) alkylation at reactive methylene groups to introduced hydrocarbon R 1  and/or R 2  groups and/or (k) interconversion of the group X by known methods. Pharmaceutical compositions of the compound I and the compounds excluded by the proviso show anti-inflammatory activity when administered orally with the usual excipients.