Patent GB-805828-A (GB)
Title: Phosphate derivatives of steroids
IPC: C07J75/00
Filed: 1955-08-03
Abstract: The invention comprises phosphate derivatives of steroid compounds having the general formul  (1) <FORM:0805828/IV (b)/1> <FORM:0805828/IV (b)/2> and salts thereof, wherein R represents a keto or b -hydroxy group, <FORM:0805828/IV (b)/3> wherein R has the above significance, R4 is a tertiary amine and n is 1 or 2, and <FORM:0805828/IV (b)/4> and <FORM:0805828/IV (b)/5> wherein R has the above significance and R3 represents a phenyl or substituted phenyl group such as a methylphenyl, chlorophenyl or nitrophenyl group, and the preparation thereof by reactions which can commence and terminate at any stage in the following synthesis:-21 - iodo - D 4 - pregnene - 17a  - ol - 3,11,20-trione or 21 - iodo - D 4 - pregnene - 11b ,17a - diol - 3,20 - dione is reacted with an organic phosphate of the general formula (R3-CH2O)2PO(OH), wherein R3 has the above significance, to form a 21-(organic phosphate)pregnene of the general formula (4) above, the 21-(organic phosphate)-pregnene is reacted with ethylene glycol or reacted with an ethylenedioxy-yielding compound in an exchange reaction to form a 3-ethylenedioxy-21-(organic phosphate)-pregnene of the general formula (3) above, the 3-ethylene-dioxy-21-(organic phosphate) is hydrogenated in the presence of a hydrogenation catalyst and a tertiary amine to form a tertiary amine salt of a 3-ethylenedioxy-21-(organic phosphate) of the general formula (2) above, and the tertiary amine salt is hydrolysed to form an 11-(keto or b  - hydroxy) - D 4 - pregnene - 17a ,21 - diol - 21 - phosphate of the general formula (1) above and optionally converted into a salt, e.g. by reaction with an aqueous solution of alkali or alkaline-earth bases or salts such as hydroxides, carbonates, bicarbonates or acetates.  The above process may be modified in that the 21-phosphate of the general formula (3) is prepared by reacting 3-ethylenedioxy-21-iodo- D 5-pregnene-17a -ol-11,20-dione or 3-ethylenedioxy-21-iodo-D 5 - pregnene - 11b ,17a  - diol - 20 - one with an organic phosphate of the general formula (R3-CH2O)2PO(OH), wherein R has the above significance.  The above process may also be modified in that the 21 - iodo - D 4 - pregnene - 17a  - ol - 3,11,20 - trione, 21 - iodo - D 4 - pregnene - 11b ,17a  - diol - 3,20 - dione, 3 - ethylenedioxy - 21 - iodo - D 5 - pregnene - 17a  - ol - 11,20 - dione or 3 - ethylenedioxy - 21 - iodo - D 5 - pregnene - 11b ,17a -diol-20-one reactant is prepared by a process claimed in Specification 805,829.  The organic phosphate reactant of the general formula (R3-CH2O)2PO(OH), wherein R has the above significance, is preferably used in the form of a salt such as the silver, sodium, potassium, barium or calcium salt or that salt of a metal which forms an insoluble iodide.  The tertiary amine used in the hydrogenation step may be N-methyl morpholine, N-methyl piperidine, dimethylaniline, diethylaniline, or trimethylamine, and suitable hydrogenation catalysts are platinum, nickel and palladium and oxides thereof or pre-reduced platinum oxide.  The hydrolysis step may be carried out with a strong acid in a suitable solvent such as acetone, methanol, ethanol, benzene or toluene, and suitable strong acids are hydrochloric, sulphuric, perchloric and p-toluenesulphonic acid. The hydrolysis may also be carried out with the aid of an ionexchange resin.  The 3-ethylene derivatives are preferably formed by reaction with ethylene glycol in the presence of an acid catalyst, or by reaction with a lower aliphatic ketone such as acetone, methyl ethyl ketone or mesityl oxide-if necessary in the presence of a strong acid such as p-toluene sulphonic acid or sulphuric acid.  In the examples: (1) 3-ethylenedioxy- D 5-pregnene - 17a ,21 - diol - 11,20 - dione - 21 - dibenzylphosphate, D 4 - pregnene - 17a ,21 - diol - 3,11,20 - trione - 21 - dibenzylphosphate, 3 - ethylenedioxy - D 5 - pregnene - 11b ,17a ,21 - triol - 20 - one - 21 - dibenzylphosphate and D 4-pregnene - 11b ,17a ,21 - triol - 3,20 - dione - 21 - dibenzylphosphate are prepared by reacting the corresponding 21-iodo compounds with silver dibenzyl phosphate; (2) 3-ethylenedioxy- D 5 - pregnene - 17a ,21 - diol - 11,20 - dione - 21 - dibenzylphosphate and 3-ethylenedioxy- D 5-pregnene - 11b ,17a ,21 - triol - 20 - one - 21 - dibenzylphosphate are prepared by reacting D 4-pregnene - 17a ,21 - diol - 3,11,20 - trione - 21 - dibenzylphosphate and D 5 - pregnene -11b ,17a ,21 - triol - 3,20 - dione - 21 - dibenzylphosphate, respectively, with mesityl oxide in the presence of p-toluene sulphonic acid; (3) the N - methylmorpholine salt of 3 - ethylenedioxy - D 4 - pregnene - 17a ,21 - diol - 11,20-dione - 21 - phosphate and of 3 - ethylene-dioxy - D 5 - pregnene - 11b ,17a ,21 - triol - 20 - one-21-phosphate are prepared by hydrogenating 3 - ethylenedioxy - D 5 - pregnene - 17a ,21 - diol - 11,20 - dione - 21 - dibenzylphosphate and 3-ethylenedioxy - D 5 - pregnene-11b ,17a ,21 - triol - 20 - one respectively in the presence of palladium oxide and N-methylmorpholine; (4) D 4 - pregnene - 17a ,21 - diol - 3,11,20 - trione - 21 - phosphate and D 4 - pregnene - 11b ,17a ,21 - triol - 20 - one - 21 - phosphate are prepared by treating the products of (3) with an ion-exchange resin; and (5) the sodium, potassium and ammonium salts of D 4 - pregnene - 17a ,21 - diol - 3,11,20 - trione - 21-phosphate and the sodium and potassium salts of D 4 - pregnene - 11b ,17a ,21 - triol - 3,20 - dione-21-phosphate are prepared. Specification 805,830 also is referred to.