Patent GB-843155-A (GB)
Title: Improvements in or relating to steroidal lactones
IPC: C07J75/00
Filed: 1957-12-30
Abstract: The invention comprises compounds of the general formula: <FORM:0843155/IV(b)/1> wherein A represents an alkylene or alkenylene radical containing 2 or 3 carbon atoms, X represents a methylene, hydroxymethylene or carbonyl radical and there is one double bond in the 4(5) or 5(10) position.  The compounds in the case where X is a methylene radical and A is an ethylene or vinylene radical may be prepared by the following method:-17 a -ethynylestradiol 3-methyl ether is carboxylated by forming a Grignard reagent and treating with carbon dioxide to form a compound of the formula: <FORM:0843155/IV(b)/2> this compound is reduced with lithium in a mixture of liquid ammonia and tertiary butyl alcohol to form compounds of the formulae:  <FORM:0843155/IV(b)/3> <FORM:0843155/IV(b)/4> these compounds on brief contact with aqueous alkanoic acid or the equivalent i.e. an acid which produces a sufficient amount of hydrogen ion upon ionisation to cause isomerization, to form compounds of the formulae: <FORM:0843155/IV(b)/5> <FORM:0843155/IV(b)/6> and these compounds are treated with mineral acid to form compounds of the formulae: <FORM:0843155/IV(b)/7> <FORM:0843155/IV(b)/8> Compounds in which A is a chain containing 3 carbon atoms can be prepared by a similar procedure.  As an alternative procedure, a 22-alcohol may be oxidised to the corresponding aldehyde with, for example, chromium trioxide in sulphuric acid, the aldehyde is then converted to the lactone by known methods.  The aldehydes may also be synthesised from acetals, thioketals, and ketals as well as by ozonolysis of the appropriate 17-alkenyl derivative e.g. 17-(3-butenyl)-19-nortestosterones and the subsequent cleavage of the ozonide with very dilute acid.  As an exception to the foregoing procedures, the carboxypropylene lactones are prepared from an appropriate 17-butenylestradiol 3-methyl ester which is reduced with lithium and t-butyl alcohol to the enol ether of the formula:  <FORM:0843155/IV(b)/9> which is then hydrolysed to the corresponding D  5(10)-3-one, then isomerised to the corresponding D  4-3-one with mineral acid, and then oxidised and lactonised by treatment with chromium trioxide or the equivalent in a ketonic medium.  The 11-oxygenated compounds are obtained by perfusion of the compounds wherein X is a methylene radical through excised, surviving, desirably lacerated, mammalian adrenal glands to form compounds in which X represents a hydroxymethylene radical which are convertible to the corresponding compounds in which X represents a carbonyl radical by mild oxidation with chromic anhydride and sulphuric acid.  Examples 1, 2, 8 and 9 exemplify the preparation of the desired compounds by methods referred to above.  The remaining examples describe alternative methods for the preparation of the desired compounds as follows:-(3) the lactone of 17 a  - (3 - carboxypropyl) - 17b  - hydroxy -19-norandrost-4-en-3-one is prepared by treating 3 - methoxy - 17 a  - ethynyl - 1,3,5(10) - estratrien17-ol with ethyl magnesium bromide and then with epoxyethane to form 3-methoxy-17 a -(4-hydroxy - 1 - butynyl)- 1,3,5(10) - estratriene - 17 - ol, hydrogenating this compound to form 3-methoxy - 17 a  - (4 - hydroxybutyl) - 1,3,5(10) - estratrien - 17 - ol, oxidising this compound with chromic anhydride to form 3-methoxy-17 a -(3-carboxypropyl) - 1,3,5(10) - estratrien - 17 - ol lactone, reducing the sodium salt of this compound with lithium and liquid ammonia to form 17 a  - (3-carboxypropyl)-17 - hydroxy - 19 - nor - androst-5(10)-en-3-one lactone and finally treating this compound with aqueous methanolic hydrogen chloride; (4) 17 a -(2-carboxyethyl)-17b -hydroxy - 19 - nor - androst - 4 - en - 3 - one lactone is prepared by reducing 17 a -carboxyethyl - 3 - methoxy - estra - 1,3,5(10) - trien - 17 b  - ol g -lactone with lithium and liquid ammonia to form 17 a -(3-hydroxy-propyl)-17b -hydroxy-19-nor-androst-4-en-3-one, and oxidising this compound with potassium dichromate in sulphuric acid ; (5) 17 a -(2-carboxyethyl)-17b -hydroxy-19-nor-androst-4-en-3-one lactone is prepared by treating 3-methoxy-2,5(10)-estradien-17-one with the Grignard reagent formed from 2-(2-bromoethyl)-1,3-dioxolane to form 17 a -(2-formylethyl) - 17b  - hydroxy - 19 - nor - androst - 4 - ene - 3-one, and oxidising this compound with potassium dichromate in sulphuric acid; (6) 17 a -(2-carboxyethyl) - 17 - hydroxy - 19 - nor - androst - 4 - en - 3 - one lactone is prepared by treating 3-methoxy-2,5(10)-estradien-17-one with the diethyl acetal of propioaldehyde in the presence of potassium to form 3-methoxy-17 a -(2-formylethynyl)-1,3,5(10)-estratrien-17-ol, hydrogenating this compound to form 3-methoxy-17 a -(2-formylethyl)-2,5(10)-estradien-17-ol, treating this compound with hydrogen chloride to form 17 a -(2 - formyl - ethyl) - 17 b  - hydroxy - 19 - nor - androst-4-en-3-one, and oxidising this compound; (7) 17 a -(2-carboxyvinyl)-17-hydroxy-19-nor-and drost-4-en-3-one lactone is prepared by treating 3-methoxy-2,5(10)-estradien-17-one with propargyl alcohol in the presence of sodium to form 3-methoxy - 17 a  - (3 - hydroxy - 1 - propynyl) - 2,5 (10) - estradien - 17 - ol, treating this compound with hydrogen chloride to form 17b -hydroxy-17 a  e(3 - hydroxy - 1 - propynyl) - 19 - androst 4 - -n - 3 - one, hydrogenating this compound to form 17b -hydroxy-17-(3-hydroxy-1-propenyl)-19-nor-androst-4-en-3-one, and oxidising this compound; and (10) 17b -hydroxy-17-(1-methyl-2-carboxyethyl)-19-nor-andros-4-en-3-one lactone is prepared by treating 3-methoxy-17 a -(1-methyl-3-hydroxypropyl)-1,3,5(10)-estratrien-17-ol with lithium in liquid ammonia, treating the resulting enol ether with hydrogen chloride to form 17b -hydroxy - 17 - (1 - methyl - 3 - hydroxypropyl) - 19 - nor - androst 4 en - 3 one, and treating this compound with chromium trioxide.