Patent GB-768123-A (GB)
Title: Compounds of the pregnane series
IPC: C07J5/00
Filed: 1953-05-05
Abstract: The invention comprises 3b  : 11a  : 17a  : 21-tetrahydroxypregnane-20-one, and 21- and 11 : 21-esters thereof, together with a process for the preparation of said esters by the addition of hydrocyanic acid to a tri-ester of 3b  : 11a  : 21 - trihydroxypregnane - 20 - one, dehydration to produce a 17 : 20 double bond followed by complete or partial hydrolysis to form 3b  : 11a  : 21 - trihydroxypregnene - 17-yl-cyanide-20 or an 11-monoester thereof, after which the compound is selectively esterified to the 21-mono- or 11 : 21-di-ester, and then treated with a hydroxylating agent, particularly osmium tetroxide followed by a reductive splitting of the osmate ester, thereby introducing a 17a -hydroxyl group.  The product may then be hydrolysed and the 21-hydroxy group re-esterified.  The 21-mono- and 11 : 21-diesters prepared as above are converted into cortisone 21-esters and 11 : 21-diesters of 11a  : 17a  : 21 - trihydroxypregnene - 4 - dione-3 : 20 respectively, by oxidation to the corresponding 3 : 11 : 20-trione (or 3 : 20-dione), followed by treatment with a halogenating agent and then a dehydrohalogenating agent.  The triester starting materials preferably possess readily saponifiable ester groups in positions 3 and 11, e.g. acetoxy, benzoyloxy, carbomethoxy, carbethoxy, carbobenzoxy, and trifluoracetoxy.  The dehydration of the cyanhydrin is preferably effected with phosphorus oxychloride in pyridine, or silver or potassium acetates, and an alternative reagent for the hydroxylation step is aqueous potassium per, manganate.  In examples: (1) 3b  : 11a  : 21-triacetoxypregnanone-20 is treated with potassium cyanide in ethanol-glacial acetic acid and the product dehydrated with phosphorus oxychloride in pyridine to yield 3b  : 11a  : 21-triacetoxypregnen - 17 - yl - cyanide - 20 after chromatography on alumina; saponification of the cyanide with aqueous methanolic potassium hydroxide yields 3b  : 11a  : 21-trihydroxypregnen-17-yl-cyanide-20 together with the corresponding 11-acetate (which is also obtained by hydrolysis with methanolic HCl) and a little of the corresponding etiocholanic acid; selective acetylation at 0 DEG  C. produces the 21-mono-acetate and the 11 : 21-diacetate respectively; hydroxylation of the 21-monoacetate with osmium tetroxide, followed by treatment with sodium sulphite gives 3b : 11a  : 17a  : 21 - tetrahydroxypregnanone - 20 21-monoacetate, which is saponified with methanolic potassium bicarbonate and converted to the 21-propionate, trimethylacetate, b -phenylpropionate and benzoate; (2) chromic acid oxidation of the tetrahydroxy 21-monoacetate from (1) yields 17a  : 21-dihydroxypregnanetrione - 3 : 11 : 20 - monoacetate - 21, which is subsequently converted into a cortisone ester as described in Specification 710,557; (3) hydroxylation of a mixture of 3b  : 11a  : 21-trihydroxypregnen - 17 - yl - cyanide - 20 21-mono- and 11 : 21-diacetates as in (1), followed by chromatography on alumina yields 3b  : 11a  : 17a  : 21 - tetrahydroxypregnanone - 20 11 : 21-diacetate, which is subsequently converted as in (2) into 11a  : 17a  : 21-trihydroxypregnandione-3 : 20 11 : 21-diacetate and then by bromination, formation of the 3-semicarbazone and treatment with pyruvic acid into 11a  : 17a  : 21 - trihydroxypregnene - 4 - dione - 3 : 20 11 : 21-diacetate.