Patent GB-750818-A (GB)
Title: 11-a-acyloxy steroids and the preparation thereof
IPC: C07J5/00
Filed: 1953-10-20
Abstract: The invention comprises 11b -acyloxy substituted pregnanes, allopregnanes, androstanes and etiocholanes and the corresponding D 4-unsaturated compounds wherein the 11b -acyloxy group contains up to 4 carbon atoms and the said compounds contain no substituent in the C ring other than the 11b -acyloxy substituent, and the preparation thereof by reacting 11b -hydroxy substituted pregnanes, allopregnanes androstanes and etiocholanes and the corresponding D 4-unsaturated compounds with an acylating agent containing the required number of carbon atoms at a temperature no higher than 50 DEG  C., e.g. at room temperature, and in the presence of a strong acid.  By "strong acid" is meant an acid having a dissociation constant equal to at least 10-2 which does not oxidize the 11b -hydroxy group, e.g. a hydrohalic acid-particularly hydrochloric acid, sulphuric, trichloroacetic or perchloric acid, or an aromatic sulphonic acid-particularly benzene- or p-, toluene - sulphonic acid.  Suitable acylating agents are ketene and isopropenyl acetate, and acetic, propionic and butyric anhydrides.  Suitable reactants are the 11b -hydroxy-20-keto pregnanes and allopregnanes.  The above process may be modified in that the reactant is a polyhydroxy substituted compound of one of the above types of steroids and the polyacyloxy compound product is treated with an alkaline hydrolysing agent to regenerate hydroxyl groups at positions other than the 11b -position.  Suitable polyhydroxy reactants are androstan-3,11b -diols and 11b -hydroxy-pregnans and allopregnans having a further hydroxyl group in at least one of the 3-, 17-, 20- and 21-positions.  Compounds which may be prepared by the processes referred to above are 11b -acyloxy-20-keto-pregnanes and allopregnanes, 11b -acyloxy-3,20 - diketo - D 4 - pregnenes having a free hydroxyl group in at least one of the 3-, 17- and, when present, 20- and 21-positions, and compounds of the general formul  <FORM:0750818/IV(a)/1> and <FORM:0750818/IV(a)/2> wherein AcO is the 11b -acyloxy group as defined above, R1 represents <FORM:0750818/IV(a)/3> <FORM:0750818/IV(a)/4> or <FORM:0750818/IV(a)/5> R2 represents hydrogen or a hydroxy or acyloxy group, and X and X represent hydrogen or a double bond.  The above processes may be used in the preparation of D 4-pregnen-11b , 17a , 21 - triol - 3,20 - dione, 11 - acetate by the following synthesis: pregnan-3a , 11b , 17a -triol-20-one is reacted with an acetylating agent, e.g. acetic anhydride, at room temperature in the presence of a strong acid as defined above, e.g. p-toluene sulphonic acid, the triacetate formed is partially hydrolysed to pregnan-11b -acetoxy-3a , 17 - diol - 20 - one by treatment with an alkali metal base, e.g. hot sodium carbonate solution or aqueous sodium hydroxide, bromine is introduced into the 21-position by reaction with bromine in an organic solvent, the 21-bromo group is hydrolysed with sodium hydroxide to form a 21-hydroxy group or is converted to a 21-acetate group or other ester group, e.g. by reaction with sodium propionate or benzoate, the 3-hydroxy group is oxidized to a 3-keto group, e.g. with N-bromoacetamide, N-bromosuccinimide, potassium chromate or chromic acid, bromine is introduced at C4 by reaction with bromine in an organic solvent, e.g. acetic acid, or by reaction, with bromine in a non-oxidizing strong acid in a tertiary alcohol mixed with an inert solvent which is miscible with the tertiary alcohol, and the product is dehydrobrominated to form the 4,5-double bond, e.g. with semicarbazide hydrochloride, sodium acetate, acetic acid or carbon dioxide, and hydrolysing the 21-acyloxy group when present with acid or alkali.  Alternatively, the pregnan-11b  - acetoxy - 3a , 17a  - diol - 20 - one prepared as above may be oxidized to form pregnan-11b -acetoxy - 17a  - ol - 3,20 - dione, bromine introduced at C4 by reaction with bromine in an organic solvent and the 4-bromo-pregnan-11b , 17a  - diol - 3,20 - dione 1 - acetate is dehydrobrominated to form D 4-pregnen 11b , 17a -diol-3,20 - dione 1 - acetate.  In the examples the following compounds are prepared by the acylation process and if necessary the subsequent hydrolysis process referred to above: pregnan-3a ,11b ,17a -triol triacetate and 11-acetate (the 11-acetate may be acetylated back to the triacetate), pregnan - 3a ,11b ,17a ,20b  - tetrol tetra-acetate, pregnan - 11b ,21 - diol - 3,20-dione diacetate and 11-acetate (the diacetate may be brominated at C4 followed by dehydrobromination to form D 4-pregnen-11b ,21-diol-3,20 - dione - 11 - acetate), allopregnan - 11b -ol - 3,20 - dione, 1 - propionate, allopregnan-11b ,17a ,20b ,21 - tetrol - 3 - one tetra-acetate, D 4 - etiocholene - 11b  - ol - 3,17 - dione 11 - acetate and androstan-3b ,11b ,17b -triol triacetate.  In addition the following compounds are obtainable: etiocholan-3a ,11b ,17b -triol 11-acetate and 3,11,17 - triacetate, androstan - and etiocholan - 3a ,11b  - diol - 17 - one 11 - acetate and 3,11 - diacetate, androstan - and etiocholan-11b  - ol - 3,17 - dione 11 - acetate, androstan- and etiocholan - 11b ,17b  - diol - 3 - one 11-acetate and 11,17-diacetate, D 4-etiocholene-11b ,17b  - diol - 3 - one 11 - acetate and 11,17-diacetate, pregnan - 3a ,11b  - diol - 20 - one 11-acetate and 3,11-diacetate, D 4-pregnen- and pregnan - 11b  - ol - 3,20 - dione 11 - acetate, pregnan - 3a ,11b ,20a  - triol 1 - acetate and 3,11,20 - triacetate, allopregnan - and pregnan - 3a ,11b ,20b  - triol 11 - acetate and 3,11,20 - triacetate, D 4 - pregnen - and pregnan - 11b ,20a  - diol - 3 - one 11 - acetate and 11,20 - diacetate, D 4 - pregnen - and pregnan - 11b ,20b  - diol - 3 - one 11 - acetate and 11,20 - diacetate, pregnan - 3a ,11b ,17a ,20b ,21-penta - ol 11 - acetate and penta-acetate, D 4-pregnen - 11b ,17a ,21 - triol - 3,20 - dione 11-acetate, 11,17 - diacetate, 11,21 - diacetate and 11,17,21 - triacetate, D 4 - pregnen - 11b ,17a ,20b , 21 - tetrol 11 - acetate and tetra-acetate, allopregnan - and pregnan - 3a ,11b ,20b ,21 - tetrol 11 - acetate and tetra-acetate, D 4 - pregnen-allopregnan - and pregnan - 11b ,20b ,21 - triol-3 - one 11 - acetate and triacetate, D 4 - pregnen - pregnan - and allopregnan - 11b ,17a ,20b -triol - 3 - one 11 - acetate and triacetate, allopregnan - 3a ,11b ,17a ,20b  - tetrol 11 - acetate and tetra-acetate, pregnan - 3a ,11b ,17a ,20b -tetrol 11 - acetate, 16a ,17a  - oxidopregnan - 3a , 11b ,21 - triol - 20 - one 11 - acetate and 3,11,21-triacetate, 16a ,17a  - oxidopregnan - 11b ,21-diol - 3,20 - dione 11 - acetate and 11,21 - diacetate and the corresponding D 4-pregnen compounds, 16a ,17a  - oxido - D 4 - pregnen - 11b -ol - 3 - one 11 - acetate and 16a ,17a  - oxidopregnan - 11b  - ol - 3,20 - dione 11-acetate.