Patent GB-1010239-A (GB)
Title: 2-oxa-3-oxo-steroids
IPC: C07J75/00
Filed: 1963-03-11
Abstract: The invention comprises (1) a process for the preparation of 2-oxa-3-oxo-steroids in which a D 1-3-oxo-steroid not having any other carbon-carbon double bonds or any primary hydroxyl groups is contacted with ozone in an inert solvent at - 70 DEG  to +30 DEG  C. until at least the stoichiometric amount of ozone is taken up and then the resulting 1-oxo-1,2-secs intermediate is reduced with an agent known for the reduction of a carbonyl group to a carbinol group; and (2) the new 2-oxa-3-oxo-steroids of the formula <FORM:1010239/C2/1> wherein R and R1 are hydrogen atoms or methyl radicals and R11 is a hydrogen atom or an alkanoyl radical of at most 6 carbon atoms, the D 4 double bond being optional and the alkynyl radical containing from 2 to 6 carbon atoms. The intermediates in process (1) are A-nor-steroid - 1 - oxo - 1,2 - secs - 2 - oic acids, their esters and/or their anhydrides with formic acid, their precise nature depending on the solvent employed.  They need not be separated prior to the reduction step, for which complex metal hydrides are the preferred reducing agents.  In this step other unhindered carbonyl groups, e.g. 17-oxo, may also be reduced.  Preferred products of process (1) are compounds of the formula <FORM:1010239/C2/2> wherein X is b -hydroxymethylene, b -alkanoyl-oxymethylene, a  - alkyl - b  - hydroxymethylene and a  - alkyl - b  - alkanoyloxymethylene, and examples describe the preparation of such compounds and of other 2-oxa-3-oxo-steroids containing various pregnane 17-side chain and also 6b -hydroxy groups. Compounds (2) may be prepared by process (1) when they do not contain a D 4 double bond or by similar processes involving cleavage of the D 1 double bond with reagents such as lead tetra-acetate and osmium tetroxide.  17b -ols resulting from the reduction process may be oxidized to 17-ones and treatment of these lactone products with alcoholic alkali metal hydroxides gives compounds such as the potassium salt of 1-hydroxy-17-oxo-1,2-secs - A - nor - 5a  - androstan - 2 - oic acid which on reaction with alkynes give compounds (2). Alternatively, the 4,5-dehydro compounds may be prepared from the corresponding 17a -alkynyl testosterones, by dehydrogenation to the 1,4-dienes, hydroxylation to the 1,2-diols, cleavage with lead tetra-acetate to give the 1,2-secs - A - norandrost - 3 - en - 2 - oic acids and reduction of these.  The 6-methyl compounds may be prepared from the corresponding 6 - methyl - 3,17 - diketo - steroids, which are converted to enol ethers and thence to 17a -alkynyl-17b -ols, these are 1,2-dehydrogenated and these are cleared and reduced.  The 19-nor compounds may be prepared from 6b ,19-epoxy-5a  - androstane - 3,17 - dione, by conversion to the 3 - dimethyl - ketal, 17 - alkynylation, hydrolysis of the ketal function, bromination and dehydrobromination to give 17a -alkynyl-6b ,19 - epoxy - 17b  - hydroxy - 5a  - androst-1-en-3-ones, reaction of these with boron trifluoride and acetic anhydride, then with alkali and finally with acetic anhydride to give 17a -alkynyl - 6b ,17b  - diacetoxy - 19 - nor - 5a  - androst - 1 - en - 3 - ones, ozonolysis of these and reduction of the resulting 1,2-secs-A-nor intermediates to give 17b -acetoxy-17a -alkynyl-6b -hydroxy - 2 - oxa - 19 - nor - 5a  - androstan - 3 - ones, reaction of these with phosphorus oxychloride to give an equilibrium mixture <FORM:1010239/C2/3> and hydrosis of this to give the 17b -ols, separated chromatographically. The 17-acylates of the invention are prepared by acylation of the 17-ols. Examples are given.