Patent GB-776427-A (GB)
Title: 4-estrene-3, 17-diol, 17-substitution products, esters thereof, and their production
IPC: C07J75/00
Filed: 1955-10-20
Abstract: The invention comprises compounds of the general formula <FORM:0776427/IV(b)/1> wherein A represents hydrogen or an aliphatic hydrocarbon radical containing less than 9 carbon atoms, and R and R1 are each hydrogen, or a benzoyl radical or an acyl radical derived from an aliphatic carboxylic acid containing 1 to 8 carbon atoms, and the preparation of the above compounds in which R represents hydrogen by the reduction of the corresponding 3-oxo substituted compounds by the Meerwein-Ponndorf-Verley reaction or by the use of an alkali metal borohydride or an alkali metal aluminium hydride, and the preparation of a 17a -alkyl-4-estrene-3, 17-diol of the above general formula, wherein said alkyl radical contains at least 2 carbon atoms, by the hydrogenation of a 17a -substituted-4-estrene-3,17-diol in which the 17a -substituent is an unsaturated aliphatic hydrocarbon radical containing 2 to 8 carbon atoms, e.g. in the presence of a noble metal catalyst such as palladium.  The acyl radical may be a formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, cyclopentanacetyl, cyclopentanpriopionyl, or cyclohexanacetyl radical.  The lower aliphatic hydrocarbon radical in the desired product may be a methyl, ethyl or a straight- or branch-chained propyl or butyl radical, an alkenyl radical such as a vinyl, allyl or butenyl radical, or an alkynyl such as an ethynyl, propynyl or butynyl radical.  The 17a -substituent of the 4-estrene-3,17-diol reactant for the hydrogenation step may be of the ethylene or acetylene type such as a vinyl, propenyl, allyl, ethynyl, propynyl or butynyl radical.  Useful starting compounds for the preparation of 17a -alkenyl and alkynyl derivatives of 4-estrene-3,17-diol are the 17a -substitution products of 19-nortestosterone in which the 17a -substituent is an unsaturated aliphatic hydrocarbon radical such as an ethynyl or allyl radical.  The 3,17-diesters of the above general formula may be prepared by usual esterification methods.  The 3-hydroxy group can be selectively esterified by using one molecular proportion of an acyl halide or anhydride. The 17-monoesters may be obtained by the reduction method referred to above using, for example, sodium borohydride as the reducing agent, esterification of the 3-hydroxy radical in the resulting compounds forms diesters which may contain different ester radicals.  In the examples, 4-estrene-3,17-diol and the corresponding 3,17-diacetoxy, 3,17-dibenzoyloxy, 17-propionoxy and 17 - (b  - cyclopentanpropionoxy) compounds, 17a -allyl-, 17a -vinyl-, 17a -methyl-and 17a  - ethynyl - 4 - estrene - 3,17 - diol, 17a -ethyl-4-estrene-3,17-diol and the corresponding 3-propionoxy and 3-hemisuccinate compounds, and 17a -propyl-4-estrene-3a ,17 (and 3b ,17)-diol are prepared.  Starting compounds.  17a -Substituted products of 19-nortestosterone, where the 17a -substituent is an unsaturated aliphatic hydrocarbon radical containing 2 to 8 carbon atoms, are prepared by a procedure involving the addition of acetylene, a homologue of acetylene, or an organo-metallic compound to a 17-keto-steroid, for example, 17a -ethynyl-19-nortestosterone can be prepared by the addition of acetylene to 3-methoxy-2,5(10)-estradiene followed by acid catalysed hydrolysis and isomerization of the resulting product, or 17a -allyl-19-nortestosterone can be prepared by the addition of allylmagnesium bromide to 3-methoxy-2,5(10)-estradien-17-one followed by acidic hydrolysis and isomerization of the product. In an example, allyl magnesium bromide is reacted with 3 - methoxy - 2,5(10) - estradien - 17 - one, the product is hydrolysed to form 17a -allyl-3-methoxy-2,5(10)-estradien-17-ol which is then heated with methanolic hydrogen chloride to form 17-allyl-19-nortestosterone. 17a -Ethyl-19-nortestosterine is prepared by treating 17a -ethynyl - 3 - methoxy - 1,3,5(10) - estratrien-17-ol with hydrogen in the presence of palladium on charcoal to form 17a -ethyl-3-methoxy-1,3,5 (10)-estratrien-17-ol, further treatment with liquid ammonia and lithium forms 17a -ethyl-3-methoxy-2,5(10)-estradien-17-ol, further treatment with acetic acid in refluxing methanol forms 17a -ethyl-3-oxo-5(10)-estren-17-ol which is then refluxed in methanolic hydrogen chloride.  17a -Propyl-19-nortestosterone is prepared by hydrogenating 17a -allyl-19-nortestosterone in the presence of palladium charcoal catalyst. 17a -ethynyl-19-nortestosterone is preparing by refluxing 3 - methoxy - 13 - methyl - 17a  - ethynyl - 1,4,6,7,8,9,11,12,13,14,16,17 - dodeca - hydro - 15H-cyclopenta[a ]phenanthren-17-ol in methanolic aqueous hydrochloric acid.