Patent GB-1276261-A (GB)
Title: Improvements in or relating to naphthyl acetic acid derivatives
IPC: C07C59/64
Filed: 1970-03-24
Abstract: 1276261 Naphthylacetic acid derivatives SYNTEX CORP 24 March 1970 [9 April 1969] 14317/70 Heading C2C Novel compounds of Formula I wherein one of R<SP>1</SP> and R<SP>2</SP> is hydrogen, the other is hydrogen, methyl, ethyl or difluoromethyl; or R<SP>1</SP> and R<SP>2</SP> taken together are methylene, halomethylene or ethylene; each of R<SP>3</SP> and R<SP>4</SP> is alkyl, fluoro, chloro, trifluoromethyl, hydroxy, a conventional hydrolysable ester, oxyether or thioether; provided that when one of R<SP>3</SP> and R<SP>4</SP> is hydroxy, oxyether or thioether, the other is the identical group or alkyl, fluoro, chloro, trifluoromethyl or a conventional hydrolysable ester; and provided when one of R<SP>3</SP> and R<SP>4</SP> is trifluoromethyl, the other is the identical group or fluoro, chloro, hydroxy, a conventional hydrolysable ester, oxyether or thioether; and the corresponding amides, esters, hydroxamic acids and pharmaceutically acceptable addition salts, are prepared by one of the following reaction schemes: (a) by treating methyl phenylacetate with at least 2 molar equivalents of a 2- substituted succinic anhydride, such as 2- methoxy succinic anhydride, and at least 2 molar equivalents of aluminium chloride in nitrobenzene or carbon disulphide to yield the corresponding methyl p-(3<SP>1</SP>-carboxy-3<SP>1</SP>-substituted-1<SP>1</SP>-oxopropyl) phenyl acetate and methyl p - (3<SP>1</SP> - carboxy - 2<SP>1 </SP>- substituted - 11 - oxopropyl) phenyl acetate derivatives which are separated and the oxo group of the 31-substituted derivative is selectively reduced with sodium borohydride to give the 1<SP>1</SP>.hydroxy derivative which is esterified, and the resulting 1-acetoxy derivative is treated with thionyl chloride, phosphorus trichloride or phosphorus pentachloride to yield the corresponding methyl p - (3<SP>1</SP> - chlorocarbonyl - 3<SP>1 </SP> -  substituted - 1<SP>1</SP>- acetoxypropyl) phenyl acetate derivative, which when treated with at least 3 molar equivalents of aluminium chloride in benzene yields the corresponding 7 - carbomethoxymethyl - 4- acetoxy - 2 - substituted - 1 - tetralone, which is selectively reduced with sodium borohydride to give the corresponding methyl 2-(5<SP>1</SP>-acetoxy-7<SP>1</SP>- substituted - 8<SP>1</SP> - hydroxy - 5<SP>1</SP>,6<SP>1</SP>,7<SP>1</SP>,9<SP>1</SP> - tetrahydro-2<SP>1</SP>-naphthyl) acetate. The latter is esterified with acetic anhydride and pyridine and selectively hydrogenolysed with a molar equivalent of hydrogen in the presence of a palladium catalyst to yield methyl 2-(5<SP>1</SP>-acetoxy - 7<SP>1 </SP>- substituted - 5<SP>1</SP>,6<SP>1</SP>,7<SP>1</SP>,8<SP>1</SP> - tetrahydro- 2<SP>1</SP>-naphthyl) acetate derivative, which is hydrolysed and esterified to the corresponding methyl 2 - (5<SP>1 </SP>- hydroxy - 7<SP>1 </SP>- substituted - 5<SP>1</SP>,6<SP>1</SP>,7<SP>1</SP>,8<SP>1</SP> - tetrahydro - 2<SP>1 </SP>- naphthyl) acetate derivative which is treated with various reagents to convert the 5-hydroxy substituent into other desired substituents by known means; (b) from a 5,7-disubstituted-1-tetralone which is heated with a dialkyl carbonate and alkali metal hydride to give the corresponding 2-alkoxycarbonyl-1-tetralones which are reacted with an alkyl α-halo-acetate to give the corresponding 2-alkoxycarbonyl-2-(alkoxycarbonylmethyl)-1-tetralone derivatives which are hydrolysed and reduced to give the desired product; (c) from a 5,7-disubstituted-2-tetralone by treatment with a 1-alkoxycarbonylalkylidene triphenyl phosphorane followed by heating with a Pd/C catalyst to give the above novel compounds; (d) the substituent in the position alpha to the carboxy group may be introduced into the α - unsubstituted compound by standard methods; and (e) in all cases carboxylic groups may be salified, esterified or amidated by known methods, or their derivatives hydrolysed to give the free acids and/or compounds may be resolved. Pharmaceutical compositions in conventional forms for oral administration and having analgesic, antipyretic and anti-inflammatory activity comprise an above novel compound and an excipient.