Patent GB-1254908-A (GB)
Title: Indanyloxy and indanylthio alkanoic acids and derivatives
Inventor: CRAGOE EDWARD JETHRO JR
IPC: C07C45/65
Filed: 1969-11-21
Abstract: 1,254,908. Indanyloxy and indanylthio alkanoic acids and derivatives. MERCK & CO. Inc. 21 Nov., 1969 [25 Nov., 1968], No. 57072/69. Heading C2C. Novel compounds of Formula I  in which A is an oxygen or sulphur atom; R is a hydrogen atom or a C 1-5  alkyl radical and R<SP>1</SP> is a hydrogen atom or a C 1-5  alkyl, mononuclear aryl, halo-substituted mononuclear aryl, or trifluoro-substituted C 1-5  alkyl radical, or R and R<SP>1</SP> together with the carbon atom to which they are attached form a cycloalkylidene radical; R<SP>2</SP> is a hydrogen atom or a C 1-5  alkyl radical; Y is an alkylene or haloalkylene radical; and each X is a hydrogen or halogen atom or a C 1-5  alkyl, trihalomethyl or acylamino radical or, taken together, two X radicals on adjacent carbon atoms of the benzene ring may be joined to form a bivalent hydrocarbon chain containing 3 or 4 carbon atoms between its points of attachment or a non-toxic pharmacologically acceptable salt, ester or amide thereof are prepared by one of the following alternative processes, viz., the dehydrohalogenation of a [1-oxo-2-haloindanyl(oxy or thio)]alkarioic acid of Formula II below; the hydrolysis of a [l-oxo-2-alkylideneindanyl(oxy or thio)]alkanoic acid ester; the etherification of a (hydroxy or mercapto)-2- alkylidene-1-indanone; and by treating a [1- oxoindanyl(oxy or thio)]alkanoic acid of Formula V below with an aldehyde, or if R and R<SP>1</SP> are H in the product a salt of a secondary amine in the presence of formaldehyde or paraformaldehyde followed by treatment of the resulting Mannish intermediate of Formula VI with a weak base; in all cases optionally followed by salt ester or amide formation. Novel compounds of Formula II  are prepared by halogenation of the novel compounds of Formula VII which are themselves prepared by cyclization of a compound of Formula X Novel compounds of Formula VIIa are prepared by reaction of a compound of Formula VII above with hydroxylamine hydrochloride and a base. Novel compounds of Formula V are prepared by hydrolysing a novel ester of Formula VIII which are themselves prepared by cyclization of a compound of Formula XI Novel amides, esters and salts of compounds of Formulµ II, VII and VIIa above are prepared by standard methods. [2 - Chloro - 4- (2 - methylenebu,tyryl)phenoxy]- acetic acid is prepared by action of aqueous NaHC0 3  on [2-chloro-4-(2-dimethylaminomethylbutyryl)phenoxy]acetic acid hydrochloride obtained by reaction of acetic acid, paraformaldehyde, dimethylamine hydrochloride and (2- chloro-4-butyrylphenoxy)acetic acid which is prepared by reaction of butyryl chloride and ochlorophenoxyacetic acid. 2 - Ethylidene - 5 - hydroxy - 6,7 - dichloro - 1- indanone is prepared by dehydrohalogenation of 2 - bromo - 2 - ethyl -5 - hydroxy - 6,7 - dichloro- 1 -indanone obtained by bromination of the 2 - ethyl - 5 - hydroxy - 6,7 - dichloro - 1- indanone which is prepared by cyclization of 2,3 - dichloro - 4 - (2 - methylenebutyryl)phenol. [3,5 - Dichloro - 4 - (ethoxycarbonylmethoxy)- phenyl]propionic acid is prepared by hydrogenation of the corresponding cinnamic acid obtained by reaction of malonic acid and ethyl 2,6-dichloro - 4 -formyl - phenoxy)acetate which is prepared by reaction of 3,5-dichloro-4-hydroxybenzaldehyde and ethyl bromoacetate. Pharmaceutical compositions in conventional forms for oral and parenteral administration comprise one or more of the novel compounds of Formulµ I, II, V, VII, VIIa and VIII or a derivative thereof mentioned above and a carrier or diluent therefor.