Patent GB-814711-A (GB)
Title: New steroids and process for their synthesis
IPC: C07J75/00
Filed: 1955-07-29
Abstract: The invention comprises lactones of 18b -hydroxy-16-oxo-18-homo-androstenes of the formula <FORM:0814711/IV (b)/1> wherein R represents a free or ketalized oxo group and X represents -CO-CH2-, -CH= CH- or: <FORM:0814711/IV (b)/2> and in which there is a double bond in the 4,5-position when R represents an oxo group and in the 5,6-position when R represents a ketalized oxo group, and the preparation thereof by submitting to an intramolecular aldol condensation a compound of the general formula <FORM:0814711/IV (b)/3> wherein R and X have the above significance and in which there is a double bond in the 4,5- or 5,6-position as indicated above.  The aldol condensation may be carried out in the presence of a condensation catalyst or condensing agent, preferably in the presence of a strong alkaline condensing agent such as an alkali metal hydroxide, alcoholate, amide or hydride, e.g. potassium hydroxide, potassium tertiary butoxide, sodamide or sodium ethoxide, or a condensing agent such as piperidine acetate or benzoate.  The aldol condensation may be carried out in a solvent e.g. dioxane or benzene. It is particularly advantageous to dry out the aldol condensation using potassium tertiary butoxide in an anhydrous medium or alcoholic potassium hydroxide.  The ketalized oxo group may be set free during the course of the reaction or by a subsequent reaction, e.g. by treatment with a mineral acid or a sulphonic acid advantageously in the presence of a ketone such as acetone or pyroacemic acid, or by treatment with warm dilute acetic acid.  In the examples: (1) the 18a --> 11 b  lactone of dl- D  4:14 -3 : 16 -dioxo - 11b  - hydroxy - 18 - carboxy - androstadiene is prepared by the aldol condensation of the lactone of 2a -acetonyl-2b -carboxymethyl-4bb  - methyl - 1 : 2 : 3 : 4 : 4aa : 4b : 5 : 6 : 7 : 9 : 10 : 10ab  - dodecahydrophenanthrene - 1 : 7 - dione - 4b  - ol, and dl - D 4 : 14 : 18 - 3 : 16 - dioxo-11b  : 18a - oxido - 18 - homoandrostatriene is prepared by the aldol condensation of a ketone of the formula <FORM:0814711/IV (b)/4> (2) the 18a  --> 11b  lactone of dl - D 5 : 14 - 3-ethylenedioxy - 11b  - hydroxy - 16 - oxo - 18-carboxy-androstadiene is prepared by the aldol condensation of 2a -acetonyl-2b -carboxymethyl-4bb  - methyl - 7 - ethylenedioxy - 1 : 2 : 3 : 4 : 4aa  : 4b : 5 : 6 : 7 : 8 : 10 : 10ab  - dodecahydrophenanthrene - 1 - one - 4b  - ol, and by reacting the D 4 : 14-compound of (1) with ethylene glycol in the presence of p-toluenesulphonic acid or with methyl-ethyl-dioxolane in the presence of p-toluenesulphonic acid; the dl- D 4 : 14 : 18 - compound of Example (1) is similarly treated; (3) dl - D  4 : 14 : 18 - 3 : 16 - dioxo - 11b  : 18a-oxido - 18a - methyl - 18 - homo - androstatriene is prepared by the aldol condensation of a compound of the formula <FORM:0814711/IV (b)/5> (4) dl - D 5 : 14 : 18 - 3 - ethylenedioxy 11b : 18a-oxido - 16 - oxo - 18a - methyl - 18 - homoandrostatriene is prepared by the aldol condensation of a compound of the formula <FORM:0814711/IV (b)/6> and by treating dl - D 4 : 14 : 18 - 3 : 16 - dioxo-11b  : 18a - oxido - 18a - methyl - 18 - homoandrostatriene with methyl-ethyl-dioxolane in the presence of p-toluenesulphonic acid.  Aldosterone derivatives are prepared by hydrogenating the 14,15-position of lactones of 18b -hydroxy-16-oxo-18-homo-androstenes of the formula <FORM:0814711/IV (b)/7> wherein R represents a free or ketalized oxo group and X represents -CO-CH2-, -CH = CH-, or: <FORM:0814711/IV (b)/8> and in which there is a double bond in the 4,5-position when R represents an oxo group and in the 5,6-position when R represents a ketalized oxo group, introducing an hydroxyacetyl group at the 17-position, degrading the group X to a free or functionally converted 13-aldehyde group with fission of the 18a : 11-oxido group, and eliminating the 16-keto group. The monolactone of 2 : 2-dicarboxymethyl-4bb -methyl - 1 : 2 : 3 : 4 : 4aa  : 4b : 5 : 6 : 7 : 9 : 10 : 10ab -dodecahydrophenanthrene - 1 : 7 - dione - 4b  - ol and the methyl ester thereof are prepared by treating 2 : 2-diallyl-4bb -methyl-1 : 2 : 3 : 4 : 4aa  : 4b : 5 : 6 : 7 : 9 : 10 : 10ab  - dodecahydrophenanthrene - 1,7 - dione - 4b  - ol with oxygen containing ozone and then with zinc dust in alcohol to form a disemiacetal of an aldehyde of the formula <FORM:0814711/IV (b)/9> and oxidizing the disemiacetal with sodium dichromate to form the desired monolactone which probably exists as an equilibrium mixture of the formulae <FORM:0814711/IV (b)/100> and, if desired, esterifying the free acid to form the methyl ester thereof.  The monolactone of 2 : 2-dicarboxymethyl-46b -methyl - 7 - ethylenedioxy - 1 : 2 : 3 : 4 : 4aa  : 4b : 5 : 6 : 7 : 8 : 10 : 10ab  - dodecahydrophenanthrene-1-one-4b -ol and the methyl ester thereof are prepared by treating the previous dodecahydrophenanthrene-1 : 7-dione-4b -ol and the methyl ester thereof with ethylene glycol and methylethyl-dioxolane respectively in the presence of p-toluenesulphonic acid.  The methyl ester be hydrolysed with aqueous potassium carbonate to form the free acid.  The free acid has the formula <FORM:0814711/IV (b)/111> The lactone of 2a -acetonyl-2b -carboxymethyl-4bb  - methyl - 7 - ethylenedioxy - 1 : 2 : 3 : 4 : 4aa  : 4b : 5 : 6 : 7 : 8 : 10 : 10ab  - dodecahydrophenanthrene-1-one-4b -ol of the formula <FORM:0814711/IV (b)/122> is prepared (1) by treating the previous monolactone free acid with oxalyl chloride and then with cadmium dimethyl; or (2) by treating the lactone of 2a -acetonyl-2b -carboxymethyl-4bb -methyl - 1 : 2 : 3 : 4 : 4aa  : 4b : 5 : 6 : 7 : 9 : 10 : 10ab -dodecahydrophenanthrene - 1,7 - dione - 4b  - ol with methyl-ethyl-dioxolane in the presence of p-toluenesulphonic acid. The lactone of 2a -acetonyl-2b -carboxymethyl-4bb  - methyl - 1 : 2 : 3 : 4 : 4aa  : 4b : 5 : 6 : 7 : 9 : 10 : 10ab  - dodecahydrophenanthrene - 1 : 7 - dione-4b -ol of the formula <FORM:0814711/IV (b)/133> is prepared: (1) by treating 2a -allyl-4bb -methyl - 2b  - carboxymethyl - 1 : 2 : 3 : 4 : 4aa  : 4b : 5 : 6 : 7 : 9 : 10 : 10ab  - dodecahydrophenanthrene - 1 : 7 - dione - 4b  - ol lactone with N-bromacetamide in a solution containing t-butanol and sodium acetate to form a bromohydrin of the formula <FORM:0814711/IV (b)/144> oxidizing the bromohydrin with chromium trioxide in glacial acetic acid to form a bromoketone of the formula <FORM:0814711/IV (b)/155> and either treating the bromoketone with sodium iodide to form an iodoketone of the formula <FORM:0814711/IV (b)/166> and treating the iodoketone with activated zinc dust in hot glacial acetic acid, or treating the bromoketone with activated zinc dust in hot glacial acetic acid; and (2) by treating 2a -allyl-4ba  - methyl - 2b  - carboxymethyl - 1 : 2 : 3 : 4 : 4aa  : 4b : 5 : 6 : 7 : 9 : 10 : 10a - dodecahydrophenanthrene - 1 : 7 - dione - 4b  - ol lactone with iodine in a solution containing glacial acetic acid and silver acetate or with iodosuccinimide in glacial acetic acid to form an iodohydrin (a) of the formula <FORM:0814711/IV (b)/177> oxidizing the iodohydrin with chromic acid to form the iodoketone of the formula in method (1), and treating the iodoketone with chromochloride.  A substituted phenanthrene of the formula <FORM:0814711/IV (b)/188> is prepared by (i) treating 2 : 2-diallyl-4ba -methyl - 1 : 2 : 3 : 4 : 4aa  : 4b : 5 : 6 : 7 : 9 : 10ab -dodecahydrophenanthrene - 1 : 7 - dione - 4b -ol with oxygen containing ozone followed immediately with activated zinc dust and dilute acetic acid, oxidizing the ozonization product with sodium dichromate to form 2b -allyl-4bb -methyl - 2b  - carboxymethyl - 1 : 2 : 3 : 4 : 4aa  : 4b : 5 : 6 : 7 : 9 : 10 : 10ab - dodecahydrophenanthrene-1 : 7-dione lactone of the formula <FORM:0814711/IV (b)/199> and a substituted phenanthrene of the formula <FORM:0814711/IV (b)/200> and converting the substituted phenanthrene by the method (2) outlined in the previous paragraph to the desired substituted phenanthrene by way of the iodohydrin of the formula <FORM:0814711/IV (b)/211> and iodoketone of the formula <FORM:0814711/IV (b)/222> and (2) treating 2 : 2 - dipropargyl - 4bb -methyl - 1 : 2 : 3 : 4 : 4aa  : 4b : 5 : 6 : 7 : 9 : 10 : 10ab  - dodecahydrophenanthrene - 1 : 7 - dione-4b -ol with N-bromoacetamide in a solution containing sodium acetate and glacial acetic acid, and treating the product with zinc dust and glacial acetic acid.  A Substituted phenanthrene of the formula <FORM:0814711/IV (b)/233> is prepared by (1) treating 2 : 2-dimethallyl-4bb  - methyl - 1 : 2 : 3 : 4 : 4 : 4aa  : 4b : 5 : 6 : 7 : 9 : 10 : 10ab  - dodecahydrophenanthrene - 1 : 7-dione - 4b  - ol with oxygen containing ozone and then with zinc dust and alcohol; and (2) by treating 2 : 2-diallyl-4bb -methyl-1 : 2 : 3 : 4 : 4aa  : 4b : 5 : 6 : 7 : 9 : 10 : 10ab  - dodecahydrophenanthrene-1 : 7-dione-4b -ol with silver acetate and iodine in glacial acetic acid to form an iodohydrin (b) of the formula <FORM:0814711/IV (b)/244> (the iodohydrin may be treated with pyridine and acetic anhydride at room temperature to form an acetylated iodohydrin of the formula <FORM:0814711/IV (b)/255> which may also be obtained directly by treating 2 : 2 - diallyl - 4b  - acetoxy - 4bb  - methyl-1 : 2 : 3 : 4 : 4aa  : 4b : 5 : 6 : 7 : 9 : 10 : 10ab -dodecahydrophenanthrene-1 : 7-dione with silver acetate and iodine in glacial acetic acid), dehalogenating the free iodohydrin (b) with lithium aluminium hydride to form substituted phenanthrenes epimeric at the 3-position of the formula <FORM:0814711/IV (b)/266> treating these epimeric substituted phenanthrenes with manganese dioxide to form a substituted phenanthrene of the formula <FORM:0814711/IV (b)/277> acetylating this substituted phenanthrene to form a substituted phenanthrene of the formula <FORM:0814711/IV (b)/288> and treating this substituted phenanthrene with chromium trioxide and