Patent GB-1453894-A (GB)
Title: Tetrahydrofluorene and trimethanoindene compounds
IPC: C07C237/30
Filed: 1974-01-17
Abstract: 1453894 Tetrahydrofluorene and trimethanoindene compounds MERCK & CO Inc 17 Jan 1974 [22 Jan 1973] 2362/74 Heading C2C Novel compounds of the Formula I in which Ar is an aryl or heterocyclic radical; R 1  is a hydrogen or halogen atom, an N-attached heterocyclic radical, or an aroyl, aryl, alkylthio, arylthio, aralkylthio, alkylamino, dialkylamino, acylamino, keto, hydroxy, alkoxy, alkenyloxy, alkynyloxy, aralkoxy, haloalkoxy, carboxy, alkoxycarbonyl, aralkoxycarbonyl, alkyl, haloalkyl, alkenyl or alkynyl radical; each of R 4 , R 5 , R 6  and R 7 , which may be similar or dissimilar, is a hydrogen atom or an alkyl, acyloxy, aryloxy, alkoxy, nitro, acylamino, alkylamino, dialkylamino, alkenyl, alkynyl, alkenyloxy, dialkylaminoalkyl, alkylthio, hydroxy, hydroxyalkyl, acyl, halo, cyano, carboxy, carboalkoxy, haloalkyl, cycloalkyl, trifluoromethyl or cycloalkyloxy radical; each of R 8  and R 9 , which may be similar or dissimilar, is a hydrogen atom or an alkyl, acyloxy, aryloxy, alkoxy, nitro, acylamino, alkylamino, dialkylamino, alkenyl, alkynyl, alkenyloxy, dialkylaminoalkyl, alkylthio, hydroxy, hydroxyalkyl, acyl, halo, cyano, carboxy, carboalkoxy, haloalkyl, cycloalkyl, trifluoromethyl or cycloalkyloxy radical; or is a trimethoxyphenyl radical; X is alkylene, alkenylene, alkynylene or oxa(-O-) and n is 0 or 1, or -(X) n -CH= is 1-phenylprop-1-en- 1 - yl - 3 - ylidene or 2 - cyclopentylprop - 1 - en-1-yl-3-ylidene; m is 1 or 2 and M is hydroxy, alkoxy, 2-hydroxyethoxy, aryloxy, aralkoxy, pivaloyloxymethyl, trityloxy, acetamidoethoxy, alkoxyalkoxyalkoxy, alkoxyalkoxy, phenoxy, NH 2 , carboxymethyleneamino, # - D - glycopyranosiduronyl, (N,N - dialkylcarbamoyl) - methylamino or NR<SP>11</SP>R<SP>11 1</SP>, where R<SP>11</SP> and R<SP>11 </SP><SP>1</SP> are hydrogen, alkyl, alkoxyalkyl, hydroxyalkyl, aryl, substituted aryl in which the substituent is alkoxy, halo or trifluoromethyl, aralkyl, dialkylaminoalkyl, cycloalkyl, benzyloxycarbonylmethyl, alkylthio, alkoxy, D-glucosyl, tetra - O - acetyl - d - glycosyl, D - galactosyl or D-mannosyl or NR<SP>11</SP>R<SP>111</SP> is morpholino, 1- piperidinyl, 1 - pyrrolidinyl, 4 - methylpiperazin - 1 - yl, 4 - phenylpiperazin - 1 - yl, 4 - (# - hydroxyethyl) - piperazin - 1 - yl or 1 - piperazinyl, or a symmetrical anhydride of such a compound in which M is hydroxy, wherein acyl includes alkanoyl, alkenoyl, sulfamoyl, carbamoyl, alkylsulfinyl, alkylsulfonyl, aroyl and dialkyl sulfamoyl, may be prepared by (1) reacting a compound II with an aldehyde R 8 R 9 -Ar-(X) n CHO in which X is other than oxa, to produce a compound I in which X is other than oxa, (ii) when X is oxa, reacting a compound II in which M is t-butoxy with ethyl formate in the presence of a strong base to form a hydroxymethylene on the central ring of the fused carbocyclic system, followed by ether formation via the sodium salt of the above intermediate using an appropriately substituted phenyl iodide, and thereafter modifying the substituents at M. Ethyl 6 - fluoro - 1,2,3,4 - tetrahydrofluorene- 3-carboxylate is prepared by reducing methyl 5 - fluoro - 2 - methyl indenyl - 3 - acetate to 5 - fluoro - 2 - methyl - 3 - indenyl - # - ethanol, which with thionyl chloride gives 5-fluoro-2- methyl - 3 - indenyl - # - ethyl chloride which with sodium cyanide forms 5 - fluoro - 2- methyl - 3 - indenyl - # - propionitrile which on hydrolysis with ethanolic hydrochloric acid produces ethyl 5 - fluoro - 2 - methylindenyl- 3-propionate which with N-bromosuccinide yields ethyl 2 - bromomethyl - 5 - fluorindenyl- 3-propionate which with potassium cyanide yields the 2-cyanomethyl compound which with ethanolic hydrochloric acid gives diethyl-5- fluoroindenyl - 2 - acetate - 3 - propionate which is cyclized to ethyl 6 - fluoro - 2 - oxo - 1,2,3,4- tetrahydrofluorene - 3 - carboxylate from which the keto-group is removed by forming ethyl 2 - 5,5<SP>1 </SP>- ethylidene - 6 - fluoro - 1,2,3,4 - tetrahydrofluorene - 3 - carboxylate and treating it with Raney nickel. Ethyl 6 - fluoro - 3 - oxo - 1,2,3,4 - tetrahydro fluorene-4-carboxylate is prepared by treating ethyl 5 - fluoro - 2 - methyl indenyl - 3 - acetate with N - bromosuccinimide followed by hydrolysis to yield 5-fluoro-2-hydroxymethylindenyl-3-acetic acid which is oxidized to 5- fluoro - 2 - carboxaldehydeindenyl - 3 - aceticacid, which with piperidine and malonic acid forms 5 - fluoroindene - 2 - vinylacetic - 3 - acetic dicarboxylic acid which is hydrogenated to 5- fluoroindene - 2 - propionic - 3 - acetic dicarboxylic acid which is esterified to its diethyl ester and cyclized to the required compound. 5 - Fluoro - [α - carboethoxy - 2,3 - trimethano]- indene is prepared by bromination of ethyl 5- fluoro - 2 - methyl indenyl - 3 - acetate to yield the 2-bromomethyl compound which is converted to the 2-cyanomethyl compound which is brominated to yield ethyl 5-fluoroindenyl - 2 - cyanomethyl - 2 - α - bromo - acetate which is cyclized to 5-fluoro-[α-carboethoxy-#- oxo-(2,3)-trimethano]-indene which is converted to the required compound by forming the #-S, S<SP>1</SP> ethylidene and treating with Raney nickel as described above in the preparation of ethyl 6 - fluoro - 1,2,3,4 - tetrahydrofluorene - 3- carboxylate. 3 - Chloro - 4 - methylthio - phenylpropargaldehyde is prepared by brominating 3-chloro-4- methyl thiocinnamaldehyde to form the α- bromocinnamaldehyde which is converted to its ketal, 1,1 - dimethoxy - 2 - bromo - 3 - (3 - chloro- 4 - methylthiophenyl) - 2 - propene and dehydrobrominated to 1,1 - dimethoxy - 3 - chloro- 4 - methylthiophenyl) - 2 - propyne which is hydrolysed to the required compound. t - Butyl - 6 - fluoro - 1,2,3,4 - tetrahydrofluorene - 3 - carboxylate is prepared by transesterification of the ethyl ester. Pharmaceutical compositions of the compounds I with the usual excipients show anti-inflammatory and antipyretic activity when administered orally, parenterally, topically or rectally.