Patent GB-591994-A (GB)
Title: Manufacture of hydrophenanthrene derivatives
IPC: C07C51/377
Filed: 1944-07-20
Abstract: Hydrophenanthrene derivatives are manufactured by treating a 1 - ketohydrophenanthrene, containing in the 2-position a hydrocarbon residue and a nitrile, acid amide or esterified carboxyl group and in the 7-position a phenolic hydroxyl group or a substituent convertible thereto, with or without other substituents, with an organo-metallic compound in order to introduce a hydrocarbon residue into the 1-position, directly or indirectly eliminating the resulting tertiary hydroxy group (after hydrogenating a non-aromatic multiple carbon linkage if necessary), and, if desired, converting the nitrile, acid amide or esterified carboxyl group into a free carboxyl group (which in turn may be esterified or converted into a salt), or converting the substituent in 7-position into a free hydroxy group (which in turn may be esterified or etherified), or both, and, if desired hydrogenating non-aromatic linkages or a double linkage of a partially unsaturated ring of the hydrophenanthrene nucleus, or both, at any stage after the reaction with the organo-metallic compound (in addition to any hydrogenation which may be necessary before elimination of the tertiary hydroxy group).  The starting materials may be derived from 1 : 2 : 3 : 4-tetrahydro-, 1 : 2 : 3 : 4 : 9 : 10-hexahydro- or 1 : 2 : 3 : 4 : 9 : 10 : 11 : 12-octahydro-phenanthrene, and may contain in the 2-position a methyl, ethyl, propyl, alkenyl or alkinyl group and a nitrile, acid amide or esterified carboxy (e.g. carbomethoxy-, carboethoxy- or carbobenzyloxy-) group, and in 7-position a phenolic hydroxy group which may be free, etherified, e.g. with methanol, ethanol, a phenol or a benzyl alcohol, or esterified with an organic or inorganic acid, or a nitro or amino group or a halogen atom.  After the introduction of a hydrocarbon residue, e.g. a methyl, ethyl, allyl, propyl, benzyl or ethinyl group, into the 1-position by the action of an organo-metallic compound, e.g. an organo-magnesium or -zinc halide or an alkyl- or alkinyl-alkali compound, the tertiary hydroxy group simultaneously formed may be eliminated directly by splitting of water with the formation of a carbon to carbon double bond (if desired by the direct action of the Grignard reagent at a raised temperature), after hydrogenation of any multiple carbon linkage in the side chain in a -position to the hydroxy group, or it may be first replaced by halogen or another ester group or by an ether group which may be eliminated by thermal decomposition or by the action of an agent capable of splitting off acids or alcohols, or the tertiary hydroxy group or halogen atom replacing it may be removed by reduction, e.g. with hydrogen in the presence of a noble metal catalyst, or with hydiodic acid in the presence of glacial acetic acid.  The conversion of the 2- or 7-substituent or both may be effected, especially in the case of esters or ethers, by hydrolysing agents, in a single stage or in two stages in either order, or, in the case of benzyl ethers, by the action of reducing agents.  The saturation of non-aromatic multiple carbon linkages may be brought about by hydrogenation, e.g. by chemical methods such as catalytic or electrolytic hydrogenation or by nascent hydrogen, or by biochemical methods, at any stage after the reaction with the organometallic compound, the saturation of multiple linkages (if any) in the hydrocarbon residue introduced in the 1-position being effected at the same time as the saturation of the double bond produced by the elimination of the tertiary hydroxy group, or as a separate operation, advantageously prior to the said elimination. The products containing a free carboxyl group may be esterified, e.g. directly with diazomethane or diazoethane or indirectly by way of the acid chloride or an alkali metal salt, or may be converted into salts, e.g. alkali or alkaline-earth metal or ammonium salts.  Those containing a free phenolic hydroxy group may be esterified with organic acids, e.g. acetic, propionic, butyric, palmitic, stearic or benzoic acid, sulphonic acids, polycarboxylic acids or carboxy-sulphonic acids, or with inorganic acids, e.g. sulphuric or phosphoric acid, or carbonic acid and its derivatives, or may be etherified, e.g. converted into glycosides, and if the ester or ether residue contains a basic group the corresponding salts with inorganic acids, and also betaine ester salts, may be prepared.  The products of the invention possess oestrogenic action whether administered parenterally or per os, those which contain a salt group being applicable especially in aqueous solution or by implantation of crystals.  In examples: (1) a solution of 7-methoxy-1-keto-2-carbomethoxy-2-methyl-1 : 2 : 3 : 4-tetrahydrophenanthrene in benzene is added to a Grignard solution from magnesium and ethyl bromide in ether, the mixture is refluxed, then cooled and decomposed with ammonium chloride, and 7-methoxy-1-ethyl-1-hydroxy-2-carbomethoxy-2-methyl-1 : 2 : 3 : 4-tetrahydrophenanthrene is isolated; the corresponding carbethoxy-compound may be made similarly; two isomeric carbomethoxy compounds are alternatively obtained by treating 7-methoxy-1-keto-2-carbomethoxy-2-methyl-1 : 2 : 3 : 4-tetrahydrophenanthrene with a solution of sodium or potassium acetylide in liquid ammonia or tert.-amyl alcohol and catalytically hydrogenating the resulting 1-ethinyl-1-hydroxy compound, e.g. in alcoholic solution in the presence of platinum; the higher-melting isomer is dehydrated by means of iodine in chloroform, and the resulting 1-ethylidine compound is hydrogenated in glacial acetic acid in the presence of palladium-animal charcoal to 7 - methoxy - 1 - ethyl - 2 - carbomethoxy - 2 - methyl-1 : 2 : 3 : 4-tetrahydrophenanthrene; the carbomethoxy and methoxy groups are converted to carboxy and hydroxy groups, either successively by heating with aqueous caustic potash and then with pyridine hydrochloride, or simultaneously by heating with alcoholic caustic potash; 7-hydroxy-1-ethyl-2-carboxy-2 - methyloctahydrophenanthrene may be similarly prepared from 7-methoxy-1-keto-2-carbethoxy-2-methyl-1 : 2 : 3 : 4 : 9 : 10 : 11 : 12-octahydrophenanthrene, and may be converted into its esters, e.g. the 7-butyrate, palmitate or benzoate; conversion of 7-methoxy - 1 - ethylidene - 2 - carbomethoxy - 2 -methyl-1 : 2 : 3 : 4-tetrahydrophenanthrene into the 7-hydroxy-1-ethyl-2-carboxy compound is alternatively effected by hydrolysing the carbomethoxy group with an alkaline melt, then hydrogenating the ethylidene group in the presence of a nickel catalyst and finally splitting the methoxy group, e.g. with hydrobromic acid; the 7-hydroxy group may be esterified, e.g. with propionic, stearic or benzoic acid or carbonic acid derivatives, or converted into glycosides, and the 2-carboxy group may be previously or subsequently esterified, e.g. directly by means of diazomethane or diazoethane or indirectly by treating an alkali metal salt with an alkyl or aralkyl halide, e.g. butyl bromide, heptyl chloride or benzyl chloride; (2) 7-methoxy-1-ethylidene-2-carbomethoxy-2-methyl-1 : 2 : 3 : 4-tetrahydrophenanthrene is heated with alcoholic caustic potash in an iron tube to produce the 7-hydroxy-2-carboxy compound, which may be hydrogenated in aqueous alcoholic alkaline solution in the presence of a nickel catalyst to the 1-ethyl compound; (3) methyl magnesium iodide is used instead of the ethyl compound in the first stage of (1), and the product is heated with anhydrous formic acid, hydrogenated in the presence of a palladium-carbon catalyst, fused with caustic potash and boiled with a mixture of glacial acetic and concentrated hydrochloric acids, yielding 7-hydroxy-1 : 2-dimethyl-2-carboxy-1 : 2 : 3 : 4-tetrahydrophenanthrene; (4) a mixture of magnesium and a magnesium-copper alloy is treated with allyl bromide in ether in the presence of iodine, and a solution in ether of 7-ethoxy-1-keto-2-carbethoxy-2-ethyl-1 : 2 : 3 : 4-tetrahydrophenanthrene and a further quantity of allyl bromide is added gradually; the resulting 7 - ethoxy - 1 - hydroxy - 1 - allyl - 2 - carbethoxy-2-ethyl-1 : 2 : 3 : 4-tetrahydrophenanthrene is treated with phosphorus oxychloride in pyridine to form the 1-allylidene compound, which is hydrolysed as in (2) to 7-hydroxy-1-allylidene-2-carboxy-2-ethyl-1 : 2 : 3 : 4-tetrahydrophenanthrene; (5) 7-ethoxy-1-allylidene-2-carbethoxy-2-ethyl-1 : 2 : 3 : 4-tetrahydrophenanthrene is hydrogenated, either in glacial acetic acid in the presence of a palladiumcarbon catalyst, or in the presence of a nickel catalyst as in (2), and the resulting 1-propyl compound is hydrolysed in one or two stages as in (2) or (1); the same end product is obtainable by hydrogenation of 7-ethoxy-1-hydroxy-1-allyl-2-carbethoxy-2-ethyl-1 : 2 : 3 : 4-tetrahydrophenanthrene, followed by elimination of water, and, in either order, hydrogenation and hydrolysis, or by using propyl magnesium bromide for the initial condensation in (4); water-soluble derivatives are obtainable by converting the product, or its 7-esters with polycarboxylic, carboxy-sulphonic or alkylated aminocarboxylic acids, into alkali, alkaline-earth or ammonium (e.g. alkylammonium or ethanolammonium) salts, or by converting the 7-hydroxy group into corresponding glycosides; (6) 7 - methoxy - 1 - keto - 2 - carbomethoxy - 2-ethyl-1 : 2 : 3 : 4-tetrahydrophenanthrene is treated with ethyl magnesium bromide, dehydrated with warm formic acid, saponified in an alkali melt, catalytically hydrogenated and hydrolysed by boiling in hydrobromic acid or heating with alcoholic caustic potash, forming 7-hydroxy-1 : 2-diethyl-2-carboxy-1 : 2 : 3 : 4-tetrahydrophenanthrene.  A list is given of further products similarly obtainable, including 7 - hydroxy - 1 - benzyl - 2 - carboxy - 2 - methyl-1 : 2 : 3 : 4-tetrahydrophenanthrene.  Samples have been furnished under Sect. 2 (5) of: (I) a mixture of stereoisomers of 7 - hydroxy - 1 - ethyl - 2 - car