Patent GB-778142-A (GB)
Title: High-molecular weight derivatives of hydroxyl group-containing steroids and a method of producing them
IPC: C07J75/00
Filed: 1954-11-19
Abstract: The invention comprises high - molecular weight derivatives of hydroxyl group-containing steroids with a sex-hormonal effect, including steroids in which the hydroxyl groups result from enolization of keto groups, said derivatives consisting of molecules in which the steroid groups present and any aromatic groups which may be present are linked together through phosphate, phosphite or thiophosphate groups, the steroid groups being linked to phosphorus through oxygen atoms and said aromatic groups being linked to phosphorus through oxygen atoms, said high molecular weight steroid derivatives being non-dialysable and soluble in aqueous alkali.  Such compounds are obtained by a process in which hydroxyl-group containing steroids with sex-hormonal effect and having at least two hydroxyl groups in the molecule, or mixtures of hydroxyl-containing steroids having sex-hormonal effect, including steroids with hydroxyl groups resulting from the enolization of keto groups with a coupling substance consisting of an aromatic compound containing at least two non-adjacent hydroxyl groups, and reacted with a phosphorylating agent, the reaction being continued until the high molecular weight phosphorus-containing derivatives (being non-dialysable and soluble in aqueous alkali) are secured, the reaction mixture being subsequently hydrolysed.  In one embodiment steroid molecules containing only a single hydroxyl group or a hydroxyl group resulting from the enolization of a keto group are reacted with a phosphorylating agent in the presence of a coupling substance containing at least 3 hydroxyl groups, whereby the molecules of the said coupling substance are linked together before, during or after coupling with the steroid.  Phosphorylating agents specified are phosphorus oxyhalide, phosphorus trihalide or thiophosphoryl halide, and phenylphosphoryl dichloride.  Coupling compounds specified are phloroglucinol, phloretin, phloridzin and the coupling substances mentioned in Specification 753,319.  Steroids mentioned are estradiol, methylandrostenediol, estrial, testosterone, pregnanediol and digitoxigenin, estrone, progesterone and 19-norsterone.  In examples: (1) estradiol is reacted at - 10 DEG  C. with phosphorus oxychloride in pyridine solution.  The product is recovered by evaporation to dryness, solution of the product in an aqueous solution of pyridine and caustic soda, dialysis, and again evaporation to dryness.  Similar examples describe the preparation of non-dialysable products by the reaction of (2) methylandrostenediol and phosphorus oxychloride; (3) estriol and phosphorus oxychloride; (11) estradiol and thiophosphoryl chloride; (13) estradiol and phosphorus oxychloride; (14) testosterone and phosphorus oxychloride; (15) estradiol and phosphorus trichloride.  In Example (4) a non-dialysable product is prepared by reacting testosterone with phosphorus oxychloride and reacting the product with phloretin to give polytestosteronephloretin phosphate.  In further examples there are reacted (5) testosterone, phosphorus oxychloride and phloroglucinol; (6) estrone, phosphorus oxychloride and phloroglucinol; (7) estrone, phosphorus oxychloride and phloretin; (8) estrone, phosphorus oxychloride and quercitin; (9) estrone, phosphorus oxychloride and phloridzin; (10) estrone, phosphorus oxychloride and rutin; (12) estradiol, resorcinol and phosphorus oxychloride.ALSO:The invention comprises high - molecular weight derivatives of hydroxyl group-containing steroids with sex-hormonal effect, including steroids in which the hydroxyl groups result from enolisation of keto-groups, said derivatives consisting of molecules, in which the steroid groups present and any aromatic groups which may be present are linked together through phosphate, phosphite, or thiophosphate groups, the steroid groups being linked to phosphorus through oxygen atoms and said aromatic groups being linked to phosphorus through oxygen atoms, said high molecular weight steroid derivatives being non-dialysable and soluble in aqueous alkali.  Such compounds are obtained by a process in which hydroxyl group-containing steroids with sex-hormonal effect and having at least two hydroxyl groups in the molecule, or mixtures of hydroxyl containing steroids having sex-hormonal effects, including steroids with hydroxyl groups resulting from the enolisation of keto groups with a coupling substance consisting of an aromatic compound containing at least two non-adjacent hydroxyl groups, are reacted with a phosphorylating agent, the reaction being continued until the high-molecular weight phosphorus-containing derivatives (being non-dialysable and soluble in aqueous alkali) are secured, the reaction mixture being subsequently hydrolysed.  In one embodiment, steroid molecules containing only a single hydroxyl group or a hydroxyl group resulting from the enolisation of a keto group are reacted with a phosphorylating agent in the presence of a coupling substance containing at least three hydroxyl groups, whereby the molecules of the said coupling substance are linked together before, during or after coupling with the steroid. Phosphorylating agents specified are phosphorus oxyhalide, phosphorus trihalide or thiophosphoryl halide, particularly the chlorides, and phenylphosphoryl dichloride.  Coupling compounds specified are phloroglucinol, phloretin, phloridzin and the coupling substances referred to in Specification 753,319, [Group IV (a)].  Steroids mentioned are extradiol, methyl-androstenediol, estriol, testosterone, pregnanediol and digitoxigenin, estrone, progesterone and 19-nortestosterone.  The fact that the products are non-dialysable is an indication that the products have a molecular weight of 2000 or above.  In examples: (1) estradiol is reacted with phosphorus oxychloride at -10 DEG  C. in pyridine solution.  The product is recovered by evaporation to dryness, redissolving the product in an aqueous solution of caustic soda and pyridine, dialysis and again evaporation to dryness.  Similar examples describe the preparation of non-dialysable products by the reaction of (2) methylandrostenediol and phosphorus oxychloride, (3) estriol and phosphorus oxychloride, (11) estradiol and thiophosphoryl chloride, (13) estradiol and phosphorus oxychloride, (14) testosterone and phosphorus oxychloride, (15) estradiol and phosphorus trichloride. In Example (4) a non-dialysable product is prepared by reacting testosterone with phosphorus oxychloride in the presence of pyridine and the product is reacted with phloretin to give polytestosteronephloretin phosphate.  In further examples there are reacted (5) testosterone, phosphorus oxychloride and phloroglucinol; (6) estrone, phosphorus oxychloride and phloroglucinol; (7) estrone, phosphorus oxychloride and phloretin; (8) estrone, phosphorus oxychloride and quercitin; (9) estrone, phosphorus oxychloride and phloridzin; (10) estrone, phosphorus oxychloride and rutin; (12) estradiol, resorcinol and phosphorus oxychloride.