Patent GB-771515-A (GB)
Title: Improvements in or relating to the manufacture of steroids
IPC: C07J13/00
Filed: 1955-04-22
Abstract: A process for the production of a 17-alphahydroxy-20-keto steroid comprises reacting a D 17(20)-steroid having a 20-hydrogen atom and a 21-carbon atom with osmium tetroxide and an organic polyvalent iodo oxide and separating the resultant 17-alpha-hydroxy-20-keto steroid from the reaction mixture.  The iodine compounds are organic iodo compounds having at least one titratable oxygen atom attached to the iodine atom, the presence of such an oxygen atom being determined by reaction with potassium iodide and estimation of the liberated iodine.  Iodo oxides referred to are those of vinyl iodides in which the double bond has been halogenated, e.g. of a -chloro-iodo-ethylene, chloro-iodofumaric acid or a -chloro-iodo-acrylic acid, aryl iodo oxides such as iodosobenzene, phenyliodosoacetate, diphenyliodyl hydroxide, phenyl iodoso acetate or propionate, iodoxybenzene, and the oxides of iodonaphthalene, iodobenzoquinone, iodoanthraquinone, iodobenzoic acid, iodobenzene sulphonic acid, iodobenzaldehyde, iodobenzophenone and iodosalicylic acid.  The aryl iodoso compounds are obtained by reaction of an aryl iodochloride with a base, e.g. sodium hydroxide.  Aryl iodoso acid addition salts can be obtained by the reaction of an aryliodide with an organic peracid.  Iodoxy compounds are obtained by boiling the corresponding iodoso compounds in water or by oxidizing an aryl iodide, e.g. with Caro's acid.  Iodyl hydroxides are obtained by reaction of an aryl iodoxy compound with normal sodium hydroxide solution at 0 DEG  C. and may be converted to salts by precipitation as a carbonate and reaction of the latter with an appropriate acid. The iodo oxide is suitably employed in an amount of 2.2 to 2.75 equivalents, and the osmium tetroxide in amount 0.001 to 0.05 equivalents.  With low concentrations no hydrolysis of the osmate ester is necessary at the end of the reaction.  As by-products of the oxidation there are obtained 17-keto-steroids and 17,20-glycols.  The oxidation is catalysed by such bases as pyridine, collidine, picoline or lutidine or by amine oxides such as those of pyridine, picoline, collidine, trimethylamine, triethylamine, N-methylmorpholine, morpholinoethanol, triethanolamine and dimethylaminoethanol.  As starting steroids are mentioned those having a 17-ethylidene, propylidene, or other alkylidene, a b -chlor- or bromethylidene, b -alkoxyethylidene, b -hydroxyethylidene, b -aryloxyethylidene or carboalkoxyethylidene group.  At the 3-, 6-, 9-, 11- and 12-positions there may be present hydroxy, keto, acyloxy, hydrocarbonoxy, halogen or oxido groups.  Preferred are D 17(20)-21-acyloxy steroids of the pregnane series, especially those oxygenated in the 3-position, acetyl radicals specified being formyl, acyl, propionyl butyryl, di- and tri-methylacetyl, valeryl, hexanoyl, octanoyl, b -cyclopentylpropionyl, benzoyl, phenylacetyl, phenylpropionyl, succinoyl and phthaloyl.  In examples: (1) 11-b -hydroxy-21-acetoxy - 4,17(20) - pregnadiene - 3 - one in butyl alcohol containing pyridine is treated with osmium tetroxide and phenyliodosoacetate in the presence of a little water.  The reaction product is chromatographed and the hydrocortisone acetate is separated from the 11b -hydroxy-4-androstene - 3,17 - dione and 11b ,17a ,20 - trihydroxy - 21 - acetoxy - 4 - pregnene - 3 - one byproducts; (2) to (10) the procedure of Example (1) is followed with variations in the amounts of water, pyridine and osmium tetroxide; (11) acetic acid is the reaction medium in a similar process; (12) iodosobenzene; and (13) iodoxybenzene are employed in similar reactions; (14) 21 - acetoxy - 4,17(20) - pregnadiene - 3,11-dione is oxygenated with iodosobenzene and osmium tetroxide to give cortisone acetate; (15) 21 - acetoxy - 4,17(20) - pregnadiene - 3-one treated with osmium tetroxide and phenyliodosoacetate by procedure similar to (1) produces 17a  - hydroxy - 21 - acetoxy - 4 - pregnene - 3,20 - dione; (16) using iodoxybenzene in aqueous acetic acid, 11a  - hydroxy - 21-acetoxy - 4,17(20) - pregnadiene - 3 - one, 11b -hydroxy - 21 - acetoxy - 1,4,17(20) - pregnatriene - 3 - one and 21 - acetoxy - 1,4,17(20)-pregnatriene - 3,11 - dione are converted to 11-epihydrocortisone acetate, 11b ,17a  - dihydroxy - 21 - acetoxy - 1,4 - pregnadiene - 3,20-dione and 17a  - hydroxy - 21 - acetoxy - 1,4-pregnadiene - 3,11,20 - trione respectively. It is stated that 9 - fluoro - and 9 - chloro - analogues of the specified starting materials are similarly converted to the corresponding 9-chloro - and 9 - fluoro - 17a  - hydroxy - 20 - keto steroids.  Starting compounds.  3,11-Diketo-4,17(20)-pregnadiene-21-oic acid methyl ester is prepared by reacting ethyl oxalate and 11-ketoprogesterone in the presence of methanolic sodium methoxide and treating the resulting sodium enolate of 21-ethoxyoxalyl-11-ketoprogesterone with potassium acetate in the presence of sodium methoxide and purifying the product by chromatography.  Similarly obtained are methyl 3-keto-11a -hydroxy-4,17(20)-pregnadiene - 21 - oate and methyl 3 - keto-4,17(20) - pregnadiene - 21 - oate.  Such esters are converted to the corresponding 3-ethylene glycol ketals by reaction in benzene with ethylene glycol in the presence of p-toluene-sulphonic acid.  3 - Ethylene glycol ketal of 11b ,21 - dihydroxy - 41,17(20) - pregnadiene - 3-one is prepared by reacting the 3-ethylene glycol ketal of 3,11-diketo-4,17(20)-pregnadiene-21-oic acid methyl ester with lithium aluminium hydride.  The 3-ethylene glycol ketals of 11a ,21-dihydroxy - 4,17(20) - pregnadiene - 3 - one and of 21 - hydroxy - 4,17(20) - pregnadiene - 3 - one are obtained similarly.  Such ketals are hydrolysed to the corresponding ketones by treatment with dilute sulphuric acid at room temperature.  11b  - Hydroxy - 21 - acetoxy - 4,17(20) - pregnadiene - 3 - one is obtained by reacting 11b ,21 - dihydroxy - 4,17(20) - pregnadiene - 3-one with acetic anhydride.  21-Acetoxy-4,17(20)-pregnadiene - 3 - one, 11a  - hydroxy - 21-acetoxy - 4,17(20) - pregnadiene - 3 - one and 11a ,21 - diacetoxy - 4,17(20) - pregnadiene are obtained in a generally similar manner.  By substituting, for example, propionic anhydride, benzoyl chloride, phthalic anhydride, succinic anhydride, oxalyl chloride, trimethylacetyl chloride, cyclopentylpropionyl chloride, diethylacetyl chloride or phenylpropionyl chloride for the acetic anhydride other similar esters can be obtained.  Formate esters are obtainable by reacting the glycols with 98 per cent formic acid. Esters of 21 - hydroxy - 4,17(20) - pregnadiene-3,11 - dione are prepared by oxidizing with chromic acid under mild conditions the corresponding esters of 11b ,21-hydroxy-4,17(20)-pregnadiene-3-one. Specifications 467,790, [Group IV], 717,130, 724,094 and 749,199 are referred to.