Patent GB-1052866-A (GB)
IPC: A61K31/57
Abstract: 1,052,866. 19-Nor- and 19-iso-nor-steroids. SYNTEX CORPORATION. July 4. 1963. No. 26545/63. Heading C2U. Novel steroids of the formulae (wherein R is hydrogen or hydrocarbon carboxylic acyl of less than 12 carbon atoms which may be substituted; R<SP>1</SP> is hydrogen, alkyl, alkenyl or alkynyl of at most 8 carbon atoms; R<SP>2</SP> is hydrogen, α-hydroxy or α-acyloxy; Y is hydrogen, #-hydroxy or keto; and X, X<SP>1</SP> and X<SP>2</SP> are hydrogen or methyl) and other 9#, 10α or 10#-19-nor steroids are prepared by treating a 9# ring A aromatic steorid having a 3-alkoxy substituent with an alkali metal in liquid ammonia followed by acid treatment to produce a mixture of the corresponding #<SP>4</SP>-3-keto-19-nor steroids, with the 9#,10α-isomer predominating, and thereafter separating by crystallization the desired isomer; and if a starting material with an 11-keto or -hydroxyl is used and an 11- desoxy compound is desired, removing the 11- hydroxy group by known means. The androstane compounds are prepared by treating a 3- alkoxy - #<SP>9(11)</SP>-dehydro estradiol 17-ester e.g. benzoate, which may also be a 1-methyl compound, with diborane and treating the product with alkaline hydrogen peroxide to give the 17- ester of a 3 - alkoxy - 11α - hydroxyestradiol, oxidizing this to the corresponding 11-one, treating this with a strong base in an aliphatic alcohol to give the corresponding 9#-H compound, converting this to the 11-unsubstituted compound by conversion to the 11-ethylene thioketal and then refluxing with Raney nickel in ethanol, converting either the 11-unsubstituted or the 11-keto compound by the process of the invention to a 19-nor-9#-testosterone and its 10α-epimer or, respectively, their 11- hydroxy derivatives (the 11-keto group may also be reduced prior to this process), and after protecting the 3-keto group, inserting the required 17 - substituents by conventional methods (an 11-keto group formed in these processes may subsequently be again reduced after protection of the 3-keto group). The 19- nor - 9# - and 9#,10α - progesterones are prepared by dehydrogenating #<SP>9(11)</SP>-dehydroprogesterone to #<SP>1,4</SP>'<SP>9(11)</SP> - pregnatriene - 3,20- dione, aromatizing this to 3-hydroxy-17#- acetyl - #<SP>1,3,5(10),9(11)</SP> -estratetraene, converting this to the 3-ether, converting this or the corresponding 1-methyl compound (prepared by dehydrogenating 3 - hydroxy - 1 - methyl- 17# - acetyl - A<SP>1</SP>'<SP>3</SP>'<SP>5(10)</SP> - estratriene to the #<SP>9(11)</SP>-compound and etherifying this) to the 20-ethylene ketal, converting this to a 3- hydroxy - 20 - ethylenedioxy #<SP>1,3,5(10)</SP> - 19- nor - pregnatrien - 11α ol ether, oxidizing this to the 11-ketone, epimerizing this to the corresponding 9#-H compound, eliminating the 11- keto group by the Wolff-Kishner method, and treating this product or the 11-keto compound or the 11-ol prepared by reduction by the process of the invention to give, after hydrolysis, a 19-nor-9#-progesterone and its 10α- epimer or, respectively, their 11-hydroxy derivatives. Oxidation of the 11-ols gives the 11-ones. The 19-nor-17α-hydroxy-9#- and 9#,10α - progesterones and - corticoids are prepared by converting 3-methoxy-#<SP>1</SP>'<SP>3,5(10)</SP>, 9(11) - 19 - nor - pregnatetraen 20 - one to the 11α-ol, converting this to the 17α-ol via the 20- enol acetate and the 17,20-epoxide, converting the product to the 20-ketal, oxidizing this to 3- methoxy - 20 - ethylenedioxy - #<SP>1,3,5(10)</SP> - 19- nor - pregnatrien - 17α - ol 11 - one, converting this to the 9#-H compound, and either reducing this by the Wolff-Kishner method to the 11- desoxy compound, converting this by the process of the invention to 19-nor-17α-hydroxy- 9#-progesterone and the 10α-H compound, and. if desired, introducing a 21-hydroxy group via the 21-iodo and 21-acetoxy compounds, or converting the 11-keto-pregnatriene by the process of the invention to 11,17α-dihydroxy-19-nor- 9#-progesterone and the 10α-H compound and, if desired, introducing a 21-hydroxy or -acyloxy group and oxidizing to the 11-ketones. The same series of reactions may also be applied to the corresponding 1-methyl compounds. The 6- and/or 16-methyl substituted compounds may be prepared by converting the appropriately 6- and/or 16-substituted 17,20; 20,21- bismethylenedioxy derivatives of prednisolone to the corresponding #<SP>9(11)</SP>-dehydro compounds, reacting these with zinc or a zinc-copper couple in aqueous pyridine to aromatize ring A and converting to the 3-methyl ethers, introducing an 11α-hydroxy group, oxidizing to the 11- ketones, epimerizing to the 9#-H compounds, and either eliminating the 11-keto group, treating the products by the process of the invention and hydrolysing the bismethylenedioxy group to give 6- and/or 16-substituted 19-nor-#<SP>4</SP>- 9# - pregnene-17α,21 - diol - 3,20 - dione and the corresponding 10α-H compounds, or treating the 11-keto compounds by the process of the invention and hydrolysing to give the corresponding hydrocortisone derivatives. The corresponding cortisones are prepared by oxidation before hydrolysis. Esterification gives the 21- esters. From all these products the 21-hydroxy group may be eliminated by conversion to the 21-tosylates and refluxing these with sodium iodide in acetic acid. In all these products the 17α-hydroxy group may be esterified, and from the 11-desoxy and 11-keto compounds it may be eliminated by reaction with zinc dust in aqueous acetic acid. The thus-produced 6- and/or 16-substituted 9#-19-nor- and 9#,10α- 19-nor-progesterones may be incubated with adrenal glands to give the corresponding 11#- hydroxy derivatives. Numerous examples illustrate these processes. Reference has been directed by the Comptroller to Specification 976,728.