Compounds of the octahydrophenanthrene series and synthesis of compounds of the cyclopentanodimethylpolyhydrophenanthrene series therefrom

摘要

FORM:0785075/IV (a)/1 FORM:0785075/IV (a)/2 FORM:0785075/IV (a)/3 FORM:0785075/IV (a)/4 FORM:0785075/IV (a)/5 FORM:0785075/IV (a)/6 FORM:0785075/IV (a)/7 FORM:0785075/IV (a)/8 FORM:0785075/IV (a)/9 FORM:0785075/IV (a)/100 FORM:0785075/IV (a)/111 FORM:0785075/IV (a)/122 FORM:0785075/IV (a)/133 FORM:0785075/IV (a)/144 FORM:0785075/IV (a)/155 FORM:0785075/IV (a)/166 FORM:0785075/IV (a)/177 The invention comprises 1-(b -carboxyethyl)-2 - keto - 14 - methyl - D 6,9,11(1) - octahydrophenanthrene (III), and its alkyl esters having up to 6 carbon atoms in the alkyl group (IV)-(see Figure), the preparation of the free acid by heating 1 - formyl - 1 - (31 - keto - 61 - carbalkoxy - hexyl) - 2 - keto - 10 - methyl - 1,2,5,8,9,10 - hexahydronaphthalene (II), in which the alkoxy group contains 1 to 6 carbon atoms with aqueous caustic alkali, e.g. sodium or potassium hydroxide, and acidifying the reaction mixture, and the preparation of the alkyl esters by treating the free acid with a substantially anhydrous alkanol containing 1 to 6 carbon atoms such as methanol, ethanol, isopropanol and butanol, in the presence of an acidic esterification catalyst. The anti-transisomers, particularly the l- and dl-anti-transisomers, of the free acid and of the alkyl esters, particularly the methyl esters, are referred to. The above process may be modified in that the 1 - formyl - 1 - 31 - keto - 61 - carbalkoxy - hexyl)-2 - keto - 10 - methyl - 1,2,5,8,9,10 - hexahydronaphthalene (II), is prepared by condensing 1-hydroxymethylene - 2 - keto - 10 - methyl-1,2,5,8,9,10 - hexahydronaphthalene (I), with an alkyl 5-keto-6-heptenoate having 1 to 6 carbon atoms in the alkyl group in the presence of a quaternary ammonium alkoxide and an inert organic solvent. The l- and dl-transmethyl esters are particularly referred to. 3 - Keto - 10,13 - dimethyl - 17 - formyl-D 4,9(11)- cyclopentanodecahydrophenanthrene - (D 9(11) - 21 - norprogesterone) (XVII) is prepared by a method which may commence at any stage in the following synthesis (see Figure). alkyl ester of 1-(b -carboxyethyl)-2-keto-14-methyl - D 6,9,11(1) - octahydrophenanthrene, (IV) referred to above is treated with the silver salt of a low molecular weight fatty acid such as of acetic acid, bromine or iodine, and a low molecular weight fatty acid such as acetic acid, and the half ester thus produced is hydrolysed with acid to form an alkyl ester of 1-(b -carboxy ethyl) - 2 - keto - 6,7 - dihydroxy - 14 - methyl-D 9,11(1) - decahydrophenanthrene (V), (the l-and dl-anti-trans methyl esters are referred to) which is then reacted with a cyclic acetalforming ketone in the presence of a dehydrating agent, e.g. copper sulphate (symmetrical ketones such as acetone, diethyl ketone, cyclohexanone and p-methylcyclohexanone are preferably used) to form a cyclic acetal of an alkyl ester of 1 - (b - carboxyethyl) - 2 - keto - 6,7 - dihydroxy-14 - methyl - D 9,11(1) - decahydrophenanthrene (VI), (the l- and dl-anti-trnas-methyl esters are referred to); compound (VI) is reduced with one molecular proportion of hydrogen in the presence of palladium as the catalyst, e.g. reduced palladium-strontium carbonate, and in the presence of an inert organic solvent, e.g. benzene, toluene, xylene, ethylbenzene, cyclohexane, a normally liquid alkane or a normally liquid aliphatic alcohol, to form a cyclic acetal of an alkyl ester of 1-(b -carboxyethyl)-2-keto-6,7-dihydroxy - 14 - methyl - D 11(1) - dodecahydrophenanthrene (VII), (the l- and dl-anti-trans methyl esters are referred to); compound VII is treated with aqueous acid under such conditions that the acetal group is hydrolysed without substantial hydrolysis of the carbalkoxy group, e.g. with acetic acid, to form an alkyl ester of 1-(b -carboxyethyl)-2-keto-6,7-dihydroxy - 14 - methyl - D 11(1) - dodecahydrophenanthrene (VIII); compound VIII is oxidized with a lower fatty acid salt of tetravelant lead, e.g. lead tetra-acetate, in the presence of a lower fatty acid, e.g. acetic acid, to form an alkyl ester of 1-(b -carboxyethyl)-2-keto-5,6-di(formylmethyl) - 6 - methyl - D 1(9) - octahydronaphthalene (IX); compound IX is dissolved in an inert solvent, e.g. an aromatic hydrocarbon solvent, and cyclized by heating in the presence of a carboxylic acid salt of an organic nitrogen containing base such as piperidine acetate to form an alkyl ester of 3-formyl-3a-methyl - 6 - (b - carboxyethyl) - 7 - keto - D 2,5a(6) octahydropentanthrene (X), (the d- and dl-antitrans methyl esters are referred to); compound X is reduced with one molecular proportion of hydrogen in the presence of palladium as catalyst, e.g. reduced palladium-strontium carbonate, and in the presence of an inert solvent which is not reduced under the reaction conditions to form an alkyl ester of 3-formyl-3a-methyl - 6 - (b - carboxyethyl) - 7 - keto - D 5a(6)-decahydropentanthrene (XI), (the d- and dl-anti-trans-methyl esters are referred to); compound XI is heated with an a ,b -glycol, e.g. ethylene glycol, in the presence of an acid condensation catalyst, e.g. a toluene sulphonic acid, and in the presence of a water-entraining agent, e.g. benzene, to form a 3-cyclic ketal of an alkyl ester of 3-formyl-3a-methyl-6-(b -carboxyethyl) - 7 - keto - D 5a(6) - decahydropentanthrene (XII is the 3-ethylene ketal derivative) (the dahd dl-anti-trans 3-ethylene ketal methyl esters are referred to); compound of the type XII is heated in a solution of an inert organic sulphate or methyl tosylate, under alkaline conditions, e.g. by adding an alkali-metal alkoxide, to form a mixture of isomeric 3-cyclic ketals of alkyl esters of 3a (a and b -dimethyl - 6 - (b - carboxethyl) - 7 - keto - D 5 - decahydropentanthrene (XIII is the 3-ethylene ketal derivative) which are then hydrolysed in the presence of water and acid to form a mixture of isomeric anti-trans 3-cyclic ketals of 3a (a and b ), 6 - dimethyl - 6 - (b - carboxyethyl) - 7 - keto - D 5-decahydropentanthrene (XIV is the 3-ethylene ketal derivative) (the mixture of 3-ethylene ketal a - and b -acids, which are particularly referred to, may be used in the next step or may be separated for use in the next step by dissolving the mixture in a low molecular weight alkanol such as methanol, adding a chemically equivalent weight of quinine, refluxing, cooling, separating the a - and b -quinine salts of 3-formyl-3a, 6 - dimethyl - 6 - (b - carboxyethyl) - 7 - keto-D 5a,6 - decahyrdopentanthrene by fractional crystallization, each quinine salt is then treated with an alkaline material more basic than quinine in an aqueous medium, the free quinine is separated, and acidification of the residue yields the separated a - or b -keto acid); a compound of the type XIV is heated in the presence of an organic carboxylic acid anhydride, e.g. acetic anhydride, and a catalytic amount of an alkali metal salt of the same carboxylic acid, e.g. sodium acetate, preferably under an atmosphere of an inert gas, to form 20-cyclic ketal derivatives of 3-keto-4-oxa-10,13 - dimethyl - 17 - formyl - D 5,9(11) - cyclopentanodecahydrophenanthrene corresponding to the a - and b -keto acids (XV is the 20-ethylene ketal derivative); a compound of the type XV is treated with methyl magnesium halide at a low temperature in diethyl ether, the reaction product is decomposed with acid and then the ether soluble product is heated with a alcohol solution of an alkali metal hydroxide to form the monoethylene ketal derivative of 3-keto - 17 - formyl - cyclopentano - 10,13 - dimethyl - D 4,9(11) - decahydrophenanthrene which is obtained only from the b -isomer of a compound of the type XV, thus giving an opportunity for separating out the unwanted a -isomer (XVI is the 20-ethylene ketal derivative) (the optically active and dl monoethylene ketals of D 9(11)-21-norprogesterone are particularly referred to); a compound of the type XVI is heated in the presence of aqueous acid to form 17-formyl-cyclopentano-10,13-dimethyl - D 4,9(11) - decahydrophenanthrene-3-one (compound XVII) (the d and dl-D 9(11)-21-norprogesterones are particularly referred to). The d-D 9(11)-21-norprogesterone may also be prepared by reacting one molar equivalent of hydrogen with d-D 9(11)16-21-norprogesterone. Starting materials. 1-(Hydroxymethylene)-2-keto - 10 - methyl - 1,2,5,8,9,10 - hexahydronaphthalene (I) is prepared by the formylation of 2 - keto - 10 - methyl - 1,2,5,8,9,10 - hexahydronaphthalene with ethyl formate in the presence of sodium methylate. The l-trans, dl-trans and dl-cis isomers are particularly referred to. The copper chelate compound of l-trans - 1 - (hydroxymethylene) - 2 - keto - 10-methyl - 1,2,5,8,9,10 - hexahydronaphthalene may be prepared by adding copper acetate solution to the free compound.