Patent GB-710482-A (GB)
Title: Steroid compounds and processes for preparing them
IPC: C07J5/00
Filed: 1948-07-29
Abstract: The invention comprises a process of treating a D 17-20-cyano-pregnene compound with osmium tetroxide, and hydrolysing the osmate ester thus obtained to produce the corresponding 17(a ) - hydroxy - 20 - keto - pregnane compound. The process may be applied to the conversion of a pregnene compound of the formula <FORM:0710482/IV (b)/1> wherein R1 is an acyloxy radical or hydrogen, R2 is a keto radical or hydrogen, and R3 is an acyloxy radical, a keto radical or hydrogen, into a pregnane compound of the formula <FORM:0710482/IV (b)/2> wherein R4 is hydroxy or hydrogen, and R5 and R6 are hydroxy, keto, or hydrogen, R5 and R6 being the same as R2 and R3 when they represent keto radicals or hydrogen, whilst when R3 is an acyloxy radical R6 is a hydroxy radical.  The D 17-20-cyano-pregnenes are obtained by treating 20-keto-pregnanes with hydrogen cyanide or one of its salts to produce the corresponding 20-hydroxy-20-cyano-pregnane compound which is then reacted with a dehydrating agent to give the D 17-20-cyanopregnene.  The preferred 20-keto-pregnanes are those containing free or esterified hydroxyl groups and may also contain other keto groups, e.g. compounds of the general formula <FORM:0710482/IV (b)/3> in which R1 and R3 are hydroxy or acyloxy radicals and R2 is a keto radical or hydrogen. Such preferred 20-keto-pregnanes include 3(a )-hydroxy - 11,20 - diketo - pregnane, 3 - acetoxy-11,20 - diketo - pregnane, 3 - benzoxy - 11,20 - diketo - pregnane, 3(a ) - hydroxy - 11,20 - diketo - 21 - hydroxy - pregnane, 3(a ) - hydroxy - 11,20 - diketo - 21 - acetoxy - pregnane, and 3(a ),21 - diacetoxy - 11,20 - diketo - pregnane.  The 20-keto-pregnane may be reacted with the hydrogen cyanide or its salt in solution in an aliphatic alcohol.  If the resulting C-20 cyanhydrin contains free primary or secondary hydroxyl groups, these may be protected prior to dehydration, by acylation or, in the case of secondary hydroxyl groups, by oxidation to a keto group, e.g. with chromic acid.  Dehydration may then be effected, e g. with phosphorus oxychloride in a solvent such as pyridine.  Reaction of the D 17-20-cyano-pregnene with osmium tetroxide yields an intermediate osmate ester which on hydrolysis with aqueous sodium sulphite solution gives an unstable 17,20 - dihydroxy - 20 - cyano - pregnane which loses hydrogen cyanide to give the 17(a )-hydroxy - 20 - keto - pregnane.  The examples include the preparation of the D 17-20-cyanopregnenes.  In these (1) 3(a )-hydroxy-11,20-diketo-pregnane is reacted in alcohol and acetic acid with potassium cyanide to give 3(a ),20 - dihydroxy - 20 - cyano - 11 - keto - pregnane which on treatment with chromic acid at room temperature yields 3,11-diketo-20-hydroxy - 20 - cyano - pregnane. Dehydration of the latter with phosphorus oxychloride in pyridine yields a mixture of nitriles, from which there is separated by chromatography D 17-3,11-diketo - 20 - cyano - pregnene.  This product is treated with osmium tetroxide in pyridine, and then aqueous sodium sulphite solution is added, giving after stirring 3,11,20 - triketo - 17(a ) - hydroxy-pregnane; (2) 3(a )-hydroxy-21-acetoxy-11,20-diketo-pregnane reacted with potassium cyanide in alcohol and acetic acid gives 3(a ) - 20 - dihydroxy - 20 - cyano - 21 - acetoxy - 11-keto-pregnane which is oxidized with chromic acid to 3,11-diketo-20-hydroxy-20-cyano-21-acetoxy-pregnane. Dehydration of the latter gives after chromatographic separation, D 17-3,11 - diketo - 20 - cyano - 21 - acetoxy - pregnene (identified by hydrolysis to the 21-hydroxy-derivative). Treatment of the 21-acetoxy compound with osmium tetroxide and pyridine, followed by the addition of sodium sulphite solution yields 3,11,20-triketo-17(a )-21-dihydroxy-pregnane.  The latter with acetic anhydride in pyridine gives the corresponding 21-acetoxy-compound; (3) 3(a )-acetoxy-11,20-diketo-pregnane, treated with potassium cyanide in alcohol and acetic acid gives 3(a )-acetoxy - 20 - hydroxy - 20 - cyano - 11 - keto - pregnane which on dehydration with phosphorus oxychloride in pyridine gives a mixture of nitriles from which is separated chromatographically D 17 - 3(a ) - acetoxy - 11 - keto - 20 - cyano pregnene.  Treatment of the latter with osmium tetroxide followed by the addition of aqueous sodium sulphite to the mixture gives after recrystallization 3(a ),17(a ) - dihydroxy - 11,20-diketo-pregnane.  The product in the mother liquors which contain this compound and its 3-acetate are treated with acetic anhydride to give pure 3(a ) - acetoxy - 17(a ) - hydroxy - 11,20 - diketo - pregnane.  Treatment of the 3(a ),17(a )-dihydroxy-11,20-diketopregnane with chromic acid yields 3,11,20-triketo - 17(a ) - hydroxy - pregnane; (4) 3(a ),21-diacetoxy - 11,20 - diketo - pregnane (prepared by reacting 3(a ) - hydroxy - 11,20 - diketo - 21 - acetoxy-pregnane with excess acetic anhydride) is reacted with potassium cyanide in acetic acid to give 3(a ),21 - diacetoxy - 11 - keto - 20 - hydroxy-20-cyano-pregnane which on dehydration with phosphorus oxychloride gives after chromatographic separation, crude D 17-3(a ),21-diacetoxy - 11 - keto - 20 - cyano - pregnene. This compound is saponified to the dihydroxy compound which is purified by crystallization and re-acetylated.  The product is treated with osmium tetroxide and then with sodium sulphite solution to give a mixture of 3(a ),17(a ),21 - trihydroxy - 11,20 - diketo - pregnane and its 3-monoacetate.  To remove osmium salts the product is dissolved in acetone and reprecipitated with ether. The product is reacted with acetic acid in pyridine to give 3(a ),21 - diacetoxy - 17(a ) - hydroxy - 11,20 - diketo-pregnane. The application of the process to the production of 17(a )-hydroxy-20-keto - pregnane from D 17 - 20 - cyano - pregnane (obtained from 20-keto-pregnane via 20-hydroxy-20-cyano-pregnane) is also outlined.  The Specification as open to inspection under Sect. 91 comprises the use of other oxidizing agents, in place of osmium tetroxide, e.g. aqueous potassium permanganate or hydrogen peroxide with a catalytic amount of osmium tetroxide.  It also includes the oxidation of the 3 - hydroxy - 17(a ) - hydroxy - 20 - keto - pregnanes to the corresponding 3 - keto - 17(a ) - hydroxy - 20 - keto - pregnanes, and the invention forming the subject of Specification 710,557.  This subject-matter does not appear in the Specification as accepted.