Patent GB-567094-A (GB)
Title: Halosteroids and preparation of the same
IPC: C07J75/00
Filed: 1942-07-13
Abstract: Cyclopentanopolyhydrophenanthrene compounds which are halogenated either in ring D or in the portion of the side chain adjacent position-17, are prepared by treating a 20-keto steroid or a D 16-20-keto steroid with chlorine or bromine.  Such compounds are either 17 : 21-dihalogen compounds or 16 : 17-dihalogen compounds. Halogenation may take place with or without a solvent and/or a halogenation catalyst.  The presence of a solvent is preferred. Halogenation of 20-keto steroids under mild conditions at room temperature results in the formation of a 17-halogen compound which on further halogenation at slightly elevated temperature yields with the same or a different halogen the 17 : 21 - dihalogen compound. Halogenation under the more vigorous conditions in the first instance leads directly to the 17 : 21-dihalogen compound.  If the cyclopentanopolyhydrophenanthrene nucleus contains a double bond or other active groups, such as keto groups, halogen will enter the nucleus at other positions in addition to the ring-D position. Suitable solvents mentioned include the liquid lower organic fatty acids, such as acetic and propionic acid, halohydrocarbons such as carbon tetrachloride, chloroform acetylene tetrachloride ethylene dibromide and in addition other solvents inert to halogen such as nitrobenzene.  The temperature for monohalogenation should be about room temperature, and for di-halogenation about 30 DEG  C. Temperatures above 100 DEG  C. are disadvantageous owing to thermal decomposition of the product.  If it is desired to produce compounds halogenated in ring-D, but unsaturated in rings A or B, indirect methods must be applied such as complete halogenation followed by treatment with potassium iodide in alcohol to reform the double bond in rings A or B.  Examples of other subsidiary reactions which may occur are the introduction of halogen atoms adjacent a keto group and the esterification of hydroxyl groups by the catalytic action of hydrohalic acids formed as a by-product during the halogenation. Treatment of the halogen compounds of this invention with strong alkali results in the formation of a D 17-21-pregnenoic acid, or a derivative at the carboxyl group thereof.  This treatment of 17 : 21-dibromo-allo-pregnanone-20 with strong methyl alcoholic potash yields a mixture of D 17-21-allo-pregnenoic acid and methyl-D 16-21-allo-pregnenoate.  These acids can be converted into functional derivatives thereof, such as acid halides, amides, azides or phenylhydrazides by the usual methods for the production of such compounds.  D 16-20-keto-pregnane compounds prepared from 17-21-dihalogen-20-keto pregnones by dehydrohalogenation followed by hydrogenation and treatment with a salt of a carboxylic acid are converted on halogenation to 16 : 17-dihalo-20-keto pregnone compounds.  This takes place smoothly at room temperature, preferably in the presence of solvents.  The reactions of the 16 : 17-dihalo-20-keto pregnone compounds are similar to those of the 17 : 21-dihalo-compounds.  They are converted into D 17-21-pregnenoic acid by excess of strong alcoholic alkali and are also acted on by dehydrogenating and dehydrohalogenating agents.  In examples: (1) (a) Bromine (1 mol.) is added to a solution of allo-pregnanone-20 in the presence of a little hydrobromic acid, the reaction being carried out at room temperature.  17-Bromo-allo-pregnanone-20 is formed.  (1) (b) The product of example (1) (a) is further treated in acetic acid solution with 1 mol. of bromine at 35 DEG  C. to form 17 : 21-dibromo-allo-pregnanone-20.  (1) (c) The 17 : 21-dibromo-allo-pregnanone-20 is treated with methanolic potassium hydroxide to form D 17-21-allo-pregnenoic acid.  (2) Allo-pregnanone-20 is treated in glacial acetic acid solution with 2 mols. of bromine at 40 DEG  C. to form 17 : 21-dibromo-allo-pregnanone-20.  (3) (a) Allo-pregnanol-3(b )-one-20 is treated with 1 mol. of bromine in glacial acetic acid solution at room temperature to form 17-bromo-allo-pregnanol-3(b )-one-20.  (3) (b) The above compound is treated with a further molecule of bromine as above, but at 40 DEG  C. to form 17 : 21-dibromo-allo-pregnanol-3(b )-one-20 acetate. (3) (c) The acetate formed in (3) (b) is treated with methanolic potassium hydroxide on the steam bath to form 3(b )-hydroxy-D 17-21-allo-pregnenoic acid. (4) (a) 3(b ) - Hydroxy-D 17-21-allo-pregnenoic acid is treated with aluminium t-butylate in toluene solution in the presence of acetone to form 3-keto-D 17-21-allo-pregnenoic acid.  (4) (b) The acid formed in (4) (a) above is treated with aluminium isopropylate in the presence of isopropyl alcohol to form 3(a )-hydroxy-D 17-21-allo-pregnenoic acid.  (5) Pregnanol-3(b )-one-20-acetate is treated with 1 mol. of bromine in acetic acid solution in presence of hydrobromic acid at 30 DEG  C. to form 17-bromo-pregnanol-3(b )-one-20 acetate which is then dibrominated as in example (3) (b). (6) Pregnanol-3(b )-one-20 is treated as in example (5) to form 17-bromo-pregnanol-3(b )-one-20 which is then dibrominated as in example (3) (b).  (7) (a) Pregnanol-3(b )-one-20 acetate is treated with 2 mols. bromine in acetic acid solution at 40 DEG  C. to form 17 : 21-dibromo-pregnanol-3(b )-one-20 acetate.  (7) (b) The acetate formed in (7) (a) is treated with fused potassium acetate in acetic acid solution to form 21-bromo-D 16-pregnenol-3(b )-one-20-acetate. (7) (c) The compound formed in (7) (b) is hydrogenated with hydrogen in dioxane solution in presence of a palladium-barium sulphate catalyst to form 21-bromo-pregnanol-3(b )-one-20-acetate.  (7) (d) The acetate formed in (7) (c) is treated with fused potassium acetate in glacial acetic acid solution to form pregnanediol-3(b )-21-one-20-diacetate.  (8) (a) Pregnanol-3(b )-one-20 is treated with 2 mols. bromine in glacial acetic acid solution at 40 DEG  C. to form 17 : 21-dibromopregnanol-3(b )-one-20.  (9) (a) 17 : 21-Dibromopregnanol-3(b )-one-20 prepared in (8) (a) above is treated with methanolic potassium hydroxide to form 3(b )-hydroxy-D 17-21-pregnenoic acid.  The same compound is obtained from the corresponding acetate as starting material, and the acid so obtained may be converted into its acetate with acetic anhydride.  (10) Allo-pregnanol-3(b )-one-20-acetate is treated with 1 mol. of bromine in acetic acid solution to form 17-bromo-allo-pregnanol-3(b )-one-20-acetate which is then dibrominated as in example (3) (b). (11) Allo-pregnanol-3(b )-one-20-acetate is treated with 1 mol. of chlorine in chloroform solution to form 17 - chloro - allo - pregnanol - 3(b ) - one - 20 - acetate, which is then dichlorinated as in example (3) (b).  (12) (a) D 5-Pregnenol-one-20 - acetate is treated with 4 mols. of bromine in glacial acetic acid solution in presence of hydrobromic acid to form 5 : 6 : 17 : 21-tetrabromo-pregnanol-3(b )-one-20-acetate.  (12) (b) The tetrabromo-compound prepared in (12) (a) is treated with sodium iodide in ethanol solution to form 17 : 21-dibromo-D 5-pregnenol-3(b )-one-20-acetate.  (12) (c) The acetate prepared in (12) (b) is treated with methanolic potassium hydroxide under reflux to produce 3(b )-hydroxy-D 5 : 17-21-pregnadienoic acid.  (12) (d) The acid produced in (12) (c) is converted into its acetate, and then oxidized with ozone in chloroform solution with intermediate protection of the nuclear double bond to form dehydroisoandrosterone.  (13) A solution of D 5-pregnenol-3(b )-one-20 in propionic acid is treated with a chloroform solution of bromine to produce 5 : 6 : 17 : 21-tetrabromo-pregnanol-3(b )-one-20-propionate.  (14) (a) D 16-Pregnenol-3(b ) acetate is treated with bromine in acetic acid solution to give 16 : 17-dibromo-pregnanol-3(b )-one-20-acetate. (16) (b) The compound produced in (16) (a) is treated with methanolic potassium hydroxide, water is added and the solution extracted with ether. The aqueous phase is acidified and extracted with ether to give 3(b )-hydroxy-D 17-21-pregnenoic acid.  The ethereal phase from the alkaline treatment is evaporated to yield methyl - 3(b ) - hydroxy-D 17-21 pregnenoate.  The Specification as open to public inspection under Sect. 91 comprises also the dehalogenation and dehydro-halogenation of the halogen compounds of this invention to give other compounds. Dehydrohalogenation of 17 : 21-dihalo-20-keto-pregnone compounds leads to the formation of 21 - halo - D 16 - unsaturated - 20 - keto-pregnance compounds which in turn can be converted into 21-acyloxy compounds and also into D 16-unsaturated-20-keto-pregnanes.  The Specification as open also describes the conversion by oxidizing agents of D 17-21-pregnenoic acids into 17-keto-androstane compounds. The oxidizing agents which are used are those capable of oxidatively rupturing carbon to carbon double bonds, and include ozone, chromic anhydride and potassium permanganate.  The oxidation may also be carried out stepwise by first hydroxylating the double bond at C17 and then oxidatively cleaving the resulting glycol.  The preferred method of oxidation is by alkaline potassium permanganate at room temperature.  Groups which are readily attacked by oxidizing agents and also nuclear double bonds are protected during such an oxidation.  The following additional examples are included.  The numbering of the examples refers to the Specification as open to inspection.  (1) (d) The acid formed in example (1) (c) is oxidized with ozone in chloroform solution to form androstanone-17 which is purified by its semi-carbazone. (3) (d) The acid prepared in example (3) (c) is converted into its acetate by treatment with acetic anhydride and then oxidized with ozone in chloroform solution to form androstanol-3(b )-one-17. (4) (c) The acid formed in example (4) (b) is oxidized with ozone in chloroform solution to form androsterone (etio-allo-cholanol-3(a )-one-17).  (8) (b) The dibromo compound prepared in example (8) (a) is refluxed with potassium