Patent GB-1201212-A (GB)
Title: Tricyclic acids, process for their manufacture and compositions containing them
IPC: C07C37/055
Filed: 1968-01-29
Abstract: 1,201,212. Carboxylic acid derivatives. CIBA Ltd. 29 Jan., 1968 [30 Jan., 1967 ; 30 Oct., 1967], No. 4432/68. Heading C2C. Novel carboxylic acid derivatives of the general formula wherein A 1  is a C 1 _ 7  alkylene or C 1-7  alkenylene radical, A 2  is a C 1-7  alkylene or C 1-7  alkenylene radical forming together with the residue Ph a 5- to 7-membered ring, Ph is an optionally substituted 1,2-phenylene group and Ar is a monocyclic aryl radical or a monocyclic monoaza-, monooxa- or monothia-cyclic radical of aromatic characteristics, and salts, esters, optionally N-substituted amides and nitriles thereof are prepared (i) by reaction of a compound of the general formula or an alkali metal salt thereof with a reactive ester of a compound of the general formula HO-A 1 -Y, wherein Y is a free or functionally converted carboxylic group, or with a ketone of the general formula A 1  = O and a tri- or tetrahalogenated methane derivative in the presence of a strong base; or (ii) by reaction of a ketone of the general formula with an Ar-Grignard reagent or an Ar-alkali metal compound under dehydrating conditions; followed optionally by converting in a resulting compound an alkenylene group A 2  into an alkylene group by reduction, or converting by methods known per se a resulting ester, amide or nitrile into the free acid, or a resulting acid or nitrile into an ester, or a resulting acid into an amide or nitrile and/or by salification of a resulting free compound or conversion of a resulting salt to the free acid. Pharmaceutical compositions having hypocholesterolemic activity comprise as active ingredient a carboxylic acid derivative of the first general formula above or a salt, ester, optionally N-substituted amide or nitrile thereof, together with a pharmaceutically suitable carrier. 6 - Hydroxy - 1 - phenyl - 1,2,3,4 - tetrahydronaphthalene is prepared by reaction of 6-methoxy - 1, 2, 3, 4 - tetrahydronaphthalene - 1 - one with magnesium and bromobenzene in ether, treatment of the resulting 1-hydroxy-6-methoxy- 1 - phenyl - 1,2,3,4 - tetrahydronaphthalene with hydrochloric acid in aqueous ethanol, hydrogenation of the 6-methoxy-1-phenyl-3,4-dihydronaphthalene so obtained in the presence of a palladium catalyst and hydrolysis of the resulting 6 - methoxy - 1 - phenyl - 1,2,3,4 - tetrahydronaphthalene with hydrochloric acid. 5- and 7 - Hydroxy - 1 - phenyl - 1,2,3,4 - tetrahydronaphthalenes are prepared analogously; and 1 - (p - chlorophenyl) - 5 - hydroxy - 1,2,3,4- tetrahydronaphthalene is prepared in the same manner, starting from p-chlorobromobenzene and 5 - methoxy - 1,2,3,4 - tetrahydro - naphthalen-1-one. Ethyl 2 - (1 - oxo - 1,2,3,4 - tetrahydro - 5- and 6 - naphthyloxy) - isobutyrates and ethyl 2(1-oxo- 2 - phenyl - 1,2,3,4 - tetrahydro - 6 - naphthyloxy)- isobutyrate are prepared by reaction of the sodium salts of 5- and 6-hydroxy-1,2,3,4-tetrahydro - naphthalen - 1 - one and 6 - hydroxy-2- phenyl - 1,2,3,4 - tetrahydronaphthalen-1-one, respectively, with ethyl 2-bromoisobutyrate. 6 - Hydroxy - 2 - phenyl - 1,2,3,4 - tetrahydronaphthalen-1-one is prepared by hydrolysis of 6 - methoxy - 2 - phenyl - 1,2,3,4 - tetrahydronaphthalen-1-one with hydrochloric acid. 6 - Hydroxy - 2 - phenyl - 1,2,3,4 - tetrahydronaphthalene is prepared by reduction of 6- methoxy - 2 - phenyl - 1,2,3,4 - tetrahydronaphthalen-1-one with sodium borohydride, followed by dehydration with hydrochloric acid and methylene chloride, hydrogenation of the 6 - methoxy - 2 - phenyl - 3,4 - dihydronaphthalene so obtained in the presence of a palladium catalyst and hydrolysis of the resulting 6-methoxy - 2 - phenyl - 1,2,3,4 - tetrahydronaphthalene with hydrochloric acid. Ethyl 2 - [3 - (3 - benzoyl - propyl) - phenyloxy]. iso - butyrate is prepared by treatment of 4 - (3 - methoxy-phenyl)-butyric acid with thionyl chloride, reaction of the resulting 4-(3- methoxy - phenyl) - butyric acid chloride with phenyl cadmium chloride, followed by hydrochloric acid, hydrolysis of the 4-(3-methoxy. phenyl)-butyrophenone so obtained with pyridine hydrochloride, conversion of the resulting 4-(3- hydroxy.phenyl).butyrophenone to the corresponding sodium salt and reaction with ethyl 2-bromo-isobutyrate.