Patent GB-864307-A (GB)
Title: Improvements relating to steroid compounds
Inventor: BERGSTROM CLARENCE G
IPC: C07J5/00
Filed: 1957-12-24
Abstract: The invention comprises steroid compounds of the general formula: <FORM:0864307/IV (b)/1> wherein Z represents on ethylene or vinylene group, and Y represents any of the groups of the formula: <FORM:0864307/IV (b)/2> wherein lower alkyl means an alkyl radical containing less than 8 carbon atoms, and the preparation thereof wherein Z represents the ethylene radical by reacting a compound of one of the formulae:  <FORM:0864307/IV (b)/3> and <FORM:0864307/IV (b)/4> wherein Y and Z have the above significance, with a hydrogen halide in a Lewis type base which acts as a hydrogen acceptor e.g. in the case of hydrogen fluoride, a suitable Lewis type base is a cyclic amine such as pyridine.  The compounds wherein Z represents the vinylene radical are prepared by dehydrogenation of the corresponding compounds wherein Z represents the ethylene radical, for example, with selenium dioxide or selenious acid in a solvent consisting of t-butanol and a small quantity of acetic acid.  In the process using the hydrogen halide in a Lewis type base, some 9(11)-dehydro compound may be formed and the crude reaction mixture may be reacted with n-bromoacetomide and aqueous perchloric acid in dioxan to convert the 9(11)-dehydro by-product into a 9a -bromo-11b -hydroxy-compound, this product is then heated with potassium acetate in ethanol or aqueous ethanol to form a 9,11-epoxide which is more readily separable by chromotography than the desired 9-halo derivative or the 9(11)-dehydro by-product.  Compounds having a 21-acyloxy group may be hydrolysed to free 21-hydroxy compounds, and products having a free 21-hydroxy group may be acylated.  In the examples the following compounds are prepared by methods described above:- 9a -chloro-21-acetoxy-17a -hydroxy-4-pregnene-3, 20-dione, 9a -fluoro-17a , 21-dihydroxy-4-pregnene-3, 20-dione and the corresponding 21-acetate, b -cyclopentylpropionate and benzoate, 9a -fluoro-17a , 21-dihydroxy-1, 4-pregnadiene-3, 20-dione and the corresponding 21-acetate, 9a -fluoro-4-androstene-3, 17-dione, 9a -fluoro-testosterone and the acetate and propionate thereof, 9a -fluoro-21-acetoxy-4-pregnene-3, 20-dione, 9a -fluoroprogesterone, 9a , 21-difluoro-17a -hydroxy-4-pregnene-3, <FORM:0864307/IV (b)/5> 20-dione and the corresponding 17a -acetate, propionate, butyrate, and b -cyclopentylpropionate compounds, and 9a -chloro-21-fluoro-17a -hydroxy-4-pregnene -3, 20-dione.  In addition the examples describe the preparation of certain compounds of the above general formula as follows: (a)9a -fluoro -4-androstene-3, 17-dione and the corresponding D 1,4-androstadiene are prepared by treating 9a -fluoro-17a , 21-dihydroxy-4-pregnene-3, 20-dione and the corresponding D 1,4-pregnadiene with sodium bismuthate; 9a -fluoro-21-chloro-4-pregnene-3, 20-dione is prepared by treating 9a -fluoro-21-hydroxy-4-pregnene-3, 20-dione with benzenesulphonyl chloride in the presence of 2, 4, 6-collidine; 9a -fluoro-17a -hydroxy-4-pregnene-3, 20-dione is prepared by treating hydrocortisone and pyridine hydrofluoride to form a mixture of 9a fluoro-17a , 21-dihydroxy-4-pregnene-3, 20-dione and 17a , 21-dihydroxy-4-, 9(11)-pregnadiene-3, 20-dione, treating this mixture with methanesulphonyl chloride and then water to precipitate the 21-methanesulphonate or 9a -fluoro-17a , 21-dihydroxy-4-pregnene-3, 20-dione, treating this compound with sodium iodide to form 9a -fluoro-17a , 21-dihydroxy-4-pregnene-3, 20-dione, treating this compound with glucial acetic acid to form a mixture of 9a -fluoro-17a -hydroxy-4-pregnene-3, 20-dione and 17a  hydroxy-4, 9(11)-pregnadiene-3, 20-dione and separating the desired 9a -fluoro-17a -hydroxy-4-pregnene-3, 20-dione, and if desired, acetylating this compound to form the corresponding 17-acetate; 9a , 21-difluoro-17a -hydroxy-4-pregnene-3, 20-dione is prepared by treating 9a -fluoro-17a , 21-dihydroxy-4-pregnene-3, 20-dione with benzene sulphonyl chloride and then collidine to form 9a -fluoro-21-chloro-17a -hydroxy-4-pregnene-3, 20-dione, treating this compound with sodium iodide to form 9a -fluoro-21-iodo-17a -hydroxy-4-pregnene-3, 20-dione, and treating this compound with silver fluoride.  The Provisional Specification states that the products obtained by reacting the 11b -hydroxy steroid reactants of the general formula above with a hydrogen halide in the presence of a solvent which acts as a hydrogen acceptor are 11-halo-substituted steroids, and the examples describe the preparation of such compounds.