Patent GB-1328570-A (GB)
Title: ,1,2,3,4,9,12-hexahydrophenanthrenes and process of making same
IPC: C07C45/67
Filed: 1970-12-08
Abstract: 1328570 1,2,3,4,9,12 - Hexahydrophenanthrene derivatives SYNTEX CORP 8 Dec 1970 [9 Dec 1969] 58238/70 Heading C2C Hexahydrophenanthrenes derivatives of the general Formula A wherein R<SP>1</SP> is methyl or ethyl; R<SP>2</SP> is carboxy, alkali metal salts thereof, carb-C 1-6 -alkoxy, formyl, hydroxymethyl and physiologically acceptable hydrolysable ester groups and labile ether groups; R<SP>3</SP> is methyl or ethyl; R<SP>4</SP> is C 1-6 -alkoxy, hydroxy or physiologically acceptable hydrolysable ester groups and labile ether groups; and R 5  is hydrogen or methyl may be prepared (a) where R<SP>4</SP> is other than hydroxy or the hydrolysable ester thereof by reducing a novel compound of partial Formula I wherein R is R<SP>4</SP> other than hydroxyl or the hydrolysable ester thereof with an alkali metal and a C 1-6 -monohydric alcohol in a C 1-6 -alkyl amine or diamine or in liquid ammonia to produce the compound of partial Formula II and aromatizing the compound II with pyridinium hydrobromide perbromide or (b) where R<SP>4</SP> is hydroxy or a conventional hydrolysable ester thereof by reducing a compound of the partial Formula I<SP>1</SP> wherein R<SP>1</SP> is hydroxy or a conventional hydrolysable ester thereof with an alkali metal in a C 1-6 -alkyl amine or diamine or in liquid ammonia in the absence of C 1-6 -monohydric alcohol followed by in optional order interconversion of the radicals R 2  and R 4  between the options of Formula I by known methods and isolation of 12α and 12# isomers.  The starting material, cis-7-methoxy-1-ethyl- 2,10 - dimethyl - 1,2,3,4 - tetrahydrophenanthrene - 2 - carboxylic acid may be prepared by hydrolysis of its methyl ester, which is prepared by electrolysis of cis 7-methoxy-1-acetyl- 2,10 - dimethyl - 1,2,3,4 - tetrahydrophenanthrene- 2-carboxylic acid, methyl ester in the presence of sulphuric acid and dioxane, the methyl ester being prepared from the free acid with MeI in dimethyl acetamide, the free acid being prepared by ring cleavage of 3-methoxy-7,15- dimethyl - 16 - oxaestra - 1,3,5(10),6,8,14- hexaen-17-one by base hydrolysis which in turn is prepared by rearrangement, using palladium on charcoal, of 3-methoxy-7,15-dimethyl - 16 - oxa - estra - 1,3,5(10),8,14 - pentaen 17-one which is prepared by cyclizing α-[2-(3- methyl - 6 - methoxy - 1,2,3,4 - tetrahydronaphthyliden) - ethyl] - α,γ - dimethyl tetronic acid with p-toluene sulphonic acid. The tetronic acid derivative above is prepared by reacting α,γ-dimethyl tetronic acid, prepared by cyclizing ethyl α-propionyl propionate using bromine, with 2 - (3 - methyl - 6 - methoxy - 1,2,3,4- tetrahydronaphthyliden)ethyl isothiouronium acetate which is prepared by reacting 3-methyl-6- methoxy - 1 - vinyl - 1 - tetralol with thiourea and acetic acid. The tetralol is prepared by reacting 3 - methoxy - 6 - methoxy - 1 - tetralone with vinyl magnesium bromide, the tetralone being prepared by the action of polyphosphoric acid on 3 - (3<SP>1</SP> - methoxybenyl)- butanoic acid which is prepared by hydrazine hydrate reduction of 3 - (3<SP>1</SP> - methoxybenzoyl) - butanoic acid which is formed by hydrogenation of 3-(3<SP>1</SP>- methoxy benzoyl)-2-butenoic acid which is prepared by reaction of 3-methoxy propiophenone with glyoxylic acid in the presence of a base. The propiophenone is prepared by reaction of diethyl cadmium and 3-methoxybenzoyl chloride which is formed from the free acid. 3 - Methyl - 6 - hydroxy - 1 - tetralone may be prepared by hydrogen bromide cleavage of 3- methyl 6-methoxy-1-tetralone. Pharmaceutical compositions of the compounds A show estrogenic and anti-fertility activity when administered orally or parenterally with the usual excipients.