Patent GB-985215-A (GB)
Title: Steroids
IPC: C07J1/00
Filed: 1961-05-19
Abstract: The invention comprises steroid lactones of the general formula <FORM:0985215/C2/1> wherein n represents 1, 2 or 3, R represents oxygen or <FORM:0985215/C2/2> R1 represents hydrogen or methyl and the A-B rings have one of the following structures <FORM:0985215/C2/3> wherein R and R1 have the above significance, unsaturated steroid acids of the general formula <FORM:0985215/C2/4> wherein n has the above significance, R11 represents hydroxy or acetoxy, R111 represents hydrogen or methyl and the A-B rings have one of the following structures <FORM:0985215/C2/5> wherein R11 has the above significance, and saturated steroid acids of the general formula <FORM:0985215/C2/6> wherein n has the above significance and the A-B rings have one of the following structures <FORM:0985215/C2/7> a process for the preparations of 17b -hydroxy-3-oxo - 5a  - androstane - 16b  - ylacetic acid lactone by oxidizing 3b ,17b -dihydroxy-5a -androstane-16b  -ylacetic acid lactone with chromic acid, and a process for the preparation of 17b -hydroxy - 3 - oxo - 4 - androstene - 16b  - ylacetic acid lactone by brominating 3b ,17b -dihydroxy-5 - androstene - 16b  - ylacetic acid lactone under acidic conditions with elemental bromine, oxidizing the resulting brominated product with chromic anhydride and removing the bromine from the brominated product with a chromous salt.  The 1,4-androstadiene lactones of the first general formula above are prepared by reducing the corresponding 4-androstene lactones with selenium dioxide or by brominating the required 17b -hydroxy-3-oxo-5a -androstane-16b -ylacetic, propionic or butyric acid, dehydrobrominating the product with dimethylformamide and acidifying the product.  In addition to these processes, the unsaturated steroid acids of the above general formula may be hydrogenated to the corresponding 17-hydroxy-16-carboxyalkyl compounds and these may be lactonized under acidic conditions.  The unsaturated steroid acid of the above general formula wherein n represents 1 and R11 and R11 both represent hydrogen may be prepared by the condensation of the required 3-hydroxy-17-oxo-steroid with glyoxylic acid and may be converted into the corresponding steroid in which n represents 2 by a subsequent step wise treatment with thionyl chloride, diazomethane and silver oxide to form respectively a corresponding 6-acid chloride, 16-diazoketone and hen the desired 16b -ylpropionic acid (if the last step is carried out in the presence of methanol the methyl 16b -ylpropionate is formed), and by repeating this procedure the next higher homologue in which n represents 3 may be prepared. All these resulting unsaturated steroid acids wherein n represents 1, 2 or 3 may be esterified to form the corresponding methyl esters, and the free acids and the methyl esters may be acetylated to form the corresponding 3-acetoxy compounds.  The saturated steroid acids of the above general formula are prepared by condensing the required 3-hydroxy-17-oxo-steroids with glyoxylic acid as above, reducing the 17-oxo group in the product to a 17-hydroxy group, acetylating the 3- and 17-hydroxy groups, and catalytically reducing the double bond. The homologues wherein n represents 2 and 3 may be prepared by the method referred to above by a stepwise treatment with thionyl chloride, diazomethane and silver oxide.  The saturated steroid acids may be lactonized, for example by reaction with potassium hydroxide. All the lactones of the above general formulae may be converted into the corresponding alkali and alkaline earth metal carboxylates containing a free 17b -hydroxy group by reaction with the stoichiometric amount of the desired base. In certain cases, the 4-androstene lactones may be acid isomerized to the corresponding 5-androstene lactones, thus 3b ,17b -dihydroxy-4-androstene-16b -ylacetic acid lactone rearranges to the corresponding 5-androstene. In the example further processes are described as follows: (a) 17b  - hydroxy - 3 - oxo - 4 - estren-16b  - ylacetic acid 16,17 - lactone is prepared by reacting estrone and glyoxylic acid to form 3-hydroxy - 17 - oxo - 1,3,5(10) - estratrien - 16-ylidenacetic acid, reducing this compound with sodium borohydride to form 3,17b -dihydroxy-1,3,5(10) - estratrien - 16 - ylidenacetic acid, methylating this compound with dimethyl sulphate to form the corresponding 3-methoxy compound, esterifying this compound to form methyl 17b  - hydroxy - 3 - methoxy -1,3,5(10)-estratrien-16-ylidenacetate, further esterifying this compound to form the corresponding 17b -acetoxy compound, hydrogenating this compound to form methyl 17b  - acetoxy - 3 - methoxy-1,3,5(10) - extratrien - 16b  - ylacetate, hydrolysing this compound with potassium hydroxide to form 17b  - hydroxy - 3 - methoxy - 1,3,5(10)-estratrien - 16b  - yl acetic acid 16,17 - lactone, treating this compound with dilute aqueous sodium hydroxide to form sodium 17b -hydroxy - 3 - methoxy - 1,3,5(10) - estratrien-16b -ylacetate, reducing this compound with liquid ammonia and lithium and treating the reduction product with hydrochloric acid: and (b) 3 - (17b  - hydroxy - 3 - oxo - 4 : estren - 16b -yl)-propionic acid 16,17-lactone is prepared by treating 3,17b  - diacetoxy - 1,3,5(10) - estratrien-16b -ylacetic acid with thinyl chloride to form the corresponding acetic acid chloride, treating this compound with diazomethane to form the corresponding diazoketone, adding to this product benzyl alcohol and 2,4,6-trimethylpyridine and heating and further pyrolysing the reaction product under vacuum to form 3-(3,17b -dihydroxy - 1,3,5(10) - estratrien - 16b  - yl) propionic acid lactone, treating this compound with methyl alcohol, sodium hydroxide and dimethyl sulphate and then sulphuric acid to form the corresponding 3-methoxylactone, converting this compound to a sodium salt with sodium hydroxide, reducing the sodium salt with lithium and liquid ammonia and acidifying the product with hydrochloric acid.  Specification 985,216 is referred to.