Patent GB-578551-A (GB)
Title: Manufacture of esters of phosphoric acid
Filed: 1942-07-21
Abstract: Esters of phosphoric acid are prepared by treating a polyoxy-compound of the oestrane, saturated or unsaturated androstane, dialkylstilbene, diphenyl-dialkyl ethane, or diphenyldialkylene ethane series which is partly esterified with an organic acid or is partly etherified, with an esterifying agent which is capable of introducing the residue of phosphoric acid. Esterifying agents mentioned include phosphorus oxychloride, pentachloride or pentoxide. In the event of a halide of phosphorus being used, there must also be present an agent capable of binding hydrogen halide.  Condensing agents such as pyridine or quinoline are preferably present.  The phosphoric ester obtained may, if desired, be subjected to partial scission to remove the organic ester group or ether residue leaving the phosphoric acid groups unattached.  This may be carried out by acid or alkaline hydrolysing agents.  Ether residues such as the benzyl residue may be split off by reducing agents.  It is stated that in general the phosphoric acid residues are more difficult to split off than organic acid residues or ether residues, thus leading to a satisfactory partial hydrolysis.  Free acid groups in the phosphoric acid residue may if desired be converted into salts, using organic or inorganic bases such as hydroxides or carbonates of alkalis, alkaline earths or ammonium, also amines such as diethylamine, ethylene diamine, mono-, di- or tri-ethanolamine, or piperidine.  Polyoxy compounds which may be used as starting materials for the process of the present invention, include oestradiol, oestriol, androsterediol, androstenediol, polyoxy compounds of the dialkyl stilbene series, of the diphenyl-dialkylethane series or of the diphenyl-dialkylene-ethane series.  The organic acid residue may be aliphatic, aromatic, alicyclic or heterocyclic or derived from a sulphonic acid.  In examples: (1) Oestradiol-3-monobenzoate is treated with phosphorus oxychloride in the presence of pyridine, to form oestradiol - 3 - benzoate - 17 - primary monophosphate. This is converted by hydrolysis with concentrated hydrochloric acid into oestradiol 17-primary mono-phosphate which on treatment with sodium bicarbonate forms the sodium salt.  In place of the benzoate, as the starting ester, there may be used the acetate, propionate, hexahydrobenzoate, toluene sulphonate, or an oestradiol-3-mono-ether such as the triphenylmethyl ether or benzyl ether.  In the case where an ether is used, the scission is effected by using a bisulphite as a reducing agent.  In addition to the sodium salt, the example also describes the preparation of the ethanolamine and the triethanolamine salts. (2) Oestradiol-17-mono-propionate is esterified with phosphorus oxychloride to form oestradiol-3-primary monophosphate-17-propionate, which is partially hydrolysed with 2N sodium carbonate.  The 3-, or 17-secondary phosphates are similarly prepared.  (3) D 5-Androstene-3 : 17-diol-3-monoacetate is esterified with phosphorus oxychloride as in example (1), and partially hydrolysed with sodium carbonate as in example (2) to form the primary 17-monophosphoric acid ester of androstenediol.  This may be oxidized to the primary testosterone-17-phosphoric acid ester.  Specification 539,506 is referred to.