Patent GB-902254-A (GB)
Title: Improvements in or relating to the preparation of steroid derivatives
Inventor: ELKS JOSEPH
IPC: C07J5/00
Filed: 1957-11-19
Abstract: 21-Phosphates of steroids of the pregnane and allopregnane series are prepared by reacting the corresponding steroid 21-halide or 21-sulphonyloxy compound with a phosphoric acid or a partially esterified phosphoric acid in the presence of an organic base which has a pKa of at least 7 in water.  The reaction is preferably conducted in an organic solvent which desirably has a dielectric constant of at least 15 and advantageously of at least 30, suitable solvents being acetonitrile, methanol, N:N-dimethylformamide and dimethylsulphoxide.  A convenient reaction temperature is 50 to 130 DEG C. and the product may be isolated by evaporating off the solvent, dissolving the residue in methanol and adding methanolic alkali metal hydroxide, separating precipitated inorganic phosphate and evaporating the solution to dryness to yield the crude alkali metal salt of the steroid phosphate.  Alternatively, the solvent may be distilled off and an aqueous solution of the product passed through a cation exchange resin, in the H+ form to give a solution of the steroid hydrogen phosphate, from which salts may be obtained by neutralization or by passage through a cation exchange resin in the salt form.  The steroids may have the general formula <FORM:0902254/IV (b)/1> wherein Z is halogen or sulphonyloxy, R1 is hydrogen, halogen or alkyl, R2 is hydrogen or alkyl, R3 is hydrogen or halogen, R4 is hydrogen, hydroxy, acyloxy or alkyl, R5 is hydrogen, hydroxy or acyloxy, X is hydrogen, hydroxy or ketonic oxygen, and Y is hydroxy, acyloxy or ketonic oxygen, and the corresponding D 1, D 4, D 1:4 and D 5 compounds.  The phosphoric acid is preferably orthophosphoric acid and it is advantageously used in excess, a suitable amount being between 4 and 16 mols per mol of steroid. The use of high proportions of acid to steroid is stated to yield a product which is predominantly mono-steroid while the use of lower proportions e.g. 4:1 or less, gives rise to increasing proportions of bis-steroid phosphates.  The phosphoric acid esters used in the process of the invention may have the formula R6R7HPO4 wherein R6 is hydrogen or aralkyl and R7 is aralkyl.  Preferred organic bases are alkylamines, particularly trialkylamines, and suitable bases include isopropylamine, diethylamine, triethylamine, tri-n-propylamine, piperidine, N-ethylpiperidine and triethanolamine. The base is conveniently used in an amount of 1 to 2 mols per mol of phosphoric acid or ester thereof.  Examples describe the preparation of hydrocortisone phosphate, solutions thereof, various sodium salts thereof and mixtures of these, the mono- and di-benzyl esters thereof and the cyclohexylammonium salt of the first of these, predisolone phosphate and sodium and cyclohexylammonium salts thereof, 3b :17a :21 - trihydroxy - 5a  - pregnane-11 : 20-dione 21-disodium phosphate, di(hydrocortisone-21-)cyclohexylammonium and sodium phosphates and the corresponding prednisolone compounds and 21-hydroxy-5a -and-5b -pregnane - 3:20 - dione 21 - disodium phosphates.  Reference is also made, in general terms, to introduction of D 4 or D 1:4 unsaturation and p  oxidation of 3b -hydroxy groups in products not having suitable physiological activity.  21-Iodo-5a -and-5b -pregnane-3:20-diones are prepared by the action of sodium iodide in acetone on the corresponding 21-methane-sulphonyloxy compounds which are in turn prepared from the 21-hydroxy compounds and methanesulphonyl chloride in pyridine.  In the Provisional Specification the phosphoric acid esters used in the process of the invention have the formula R1R2HPO4 where R1 and R2 are hydrogen, alkyl, hydroxyalkyl, aryl or aralkyl.  Specification 902,255 is referred to.