Patent GB-607134-A (GB)
Title: Manufacture of hydrophenanthrene carboxylic acids and derivatives thereof
IPC: C07C62/34
Filed: 1945-11-15
Abstract: Hydrophenanthrene carboxylic acids or derivatives thereof are manufactured by treating a naphthalene derivative, which contains in the 6-position a substituent convertible into a phenolic hydroxy group (e.g. a hydroxy group etherified 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 nitro or amino group or a halogen atom), in the 2-position a hydrogen atom capable of taking part in a condensation reaction, and in the 1-position the group <FORM:0607134/IV(b)/1> (wherein X represents an ethylene bridge, R1 a hydrogen atom or a hydrocarbon radical, R2 an esterified carboxyl group, a nitrile group or an acid amide group and R3 a substituted or unsubstituted hydrocarbon radical), and which may be partially hydrogenated in the nucleus and may contain further substituents (e.g. alkyl or halogen) in the nucleus or the side chain, with a cyclizing agent (if desired after first converting the keto group into a secondary or tertiary carbinol group by the action of hydrogen, including hydrogen originating from the presence of agents yielding it, or by reaction with an organo-metallic compound), and, when necessary, eliminating a tertiary hydroxy group so formed either immediately or by way of an intermediate product, and, if desired, treating the product with a hydrogenating agent and/or an agent capable of converting into a phenolic hydroxyl group the substituent so convertible or of converting the esterified carboxyl, nitrile or amide group into a free carboxyl group.  The direct cyclization may (depending on the condensing agent or reaction conditions or both) be effected with elimination of water, in which case the double bond formed may be saturated by means of hydrogen in alkaline medium, or without elimination of water, in which case the resulting hydroxy group may be removed directly by splitting off water or by reduction (e.g. by means of hydrogen in the presence of a noble metal catalyst or of hydriodic acid in the presence of glacial acetic acid), or indirectly by replacing it by halogen or another ester group or an ether group and removing the new substituent by thermal decomposition or treatment with an agent capable of eliminating an acid or an alcohol, or, in the case of halogen, by reduction.  In the indirect cyclization, the preliminary conversion of the keto group may be effected by means of hydrogen (e.g. in the nascent or the catalytically activated state) or an aluminium alcoholate or phenolate, or of an organo-metallic compound such as an alkyl-, alkenyl- or alkinyl-magnesium-halide or an alkinyl-alkali compound or an agent capable of converting the <FORM:0607134/IV(b)/2> where R represents an aralkyl or aryl group, and the subsequent cyclization may be carried out immediately or by way of an intermediate product. Suitable cyclizing agents for either process are: more or less concentrated sulphuric acid, phosphoric acid, phosphorus oxychloride or phosphorus pentoxide, or mixtures of these substances, alone or in the presence of organic solvents, e.g. glacial acetic acid or benzene.  Hydrolysable groups may undergo hydrolysis simultaneously with the cyclization, or ester or ether groups may be subsequently treated with hydrolysing agents or aluminium halides or pyridine salts, or, for the elimination of benzyl groups, with reducing agents.  Hydrogenation following the cyclization may be effected catalytically in the presence of a large excess of an alkali hydroxide.  Free hydroxy groups present in the products may be esterified or etherified and free carboxyl groups esterified or converted into salts, e.g. alkali or alkaline-earth metal or ammonium salts.  Examples illustrate the various features of the invention, using the following starting materials: (1) 5-(61-methoxy-naphthyl-11) -3-methyl-3-carbomethoxypentane-2-one; (2) and (3) 6-(61-methoxynaphthyl-11)-4 - methyl - 4 - carbomethoxyhexane - 3 - one; (4) 5 - (61 - methoxynaphthyl - 11) - 3 - carbethoxy - pentanone-(2); (5) 5-(61-methoxynaphthyl-11)-3 - methyl - 3 - carbethoxypentanone - (2).  Specification 591,994 is referred to. Samples have been furnished under Sect. 2 (5) of: (I) 7-methoxy-1-ethoxy-2-methyl-2-carbethoxy-1 : 2 : 3 : 4-tetrahydrophenanthrene, prepared by treating the corresponding free carboxylic acid with excess of oxalyl chloride to form the acid chloride and boiling this with ethyl alcohol; (II) 7-ethoxy-1-ethyl-2-methyl-2-carboxy-1 : 2 : 3 : 4-tetrahydrophenanthrene, prepared by the action of diethyl sulphate on the 7 - hydroxy - 2 - carbomethoxy compound followed by hydrolysis of the carbomethoxy group; (III) 7-n-propyloxy-1-ethyl-2-methyl-2-carboxy - 1 : 2 : 3 : 4 - tetrahydrophenanthrene, prepared by the action of n-propyl bromide, followed by hydrolysis, from the corresponding 7 - hydroxy - 2 - carbomethoxy compound (obtained by treating 7-hydroxy-1-ethyl-2-methyl-2 - methyl - 2 - carboxy - 1 : 2 : 3 : 4 - tetrahydrophenanthrene with diazomethane).  Naphthalene derivatives.-The starting materials described above are obtainable by condensing the corresponding 1-(b -halogen-ethyl) compounds with an aliphatic b -ketocarboxylic acid, or ester, amide or nitrile thereof, containing at least one hydrogen atom in the a -position, and, when R1 is hydrogen, subsequently replacing it, if desired, by a hydrocarbon radical.  Thus, the starting materials of the examples above may be made by: (1) heating 1-(b -bromoethyl)-6-methoxynaphthalene with acetoacetic acid methyl ester in benzene in the presence of a solution of potassium in methyl alcohol and methylating the product with methyl iodide in benzene in the presence of sodium methoxide; (2) condensing 1 - (b -iodoethyl) - 6 - methoxynaphthalene with propionylacetic acid methyl ester and methylating the product; (4) condensing 1-(b -iodoethyl)-6-methoxynaphthalene with ethyl acetoacetate.  Reference is also made to the condensation of 1-(b -halogen-ethyl)-6-alkoxynaphthalenes with b -ketoadipic ester.  The Specification as open to inspection under Sect. 91 comprises also a list of further products obtainable by the process of the invention and a table of additional substituents which may be present in the 1-, 2- and 7-positions of such compounds.  This subject-matter does not appear in the Specification as accepted.