Patent GB-508024-A (GB)
Title: Production and purification of compounds of the suprarenal cortical hormone series
IPC: C07J75/00
Filed: 1937-12-23
Abstract: 508,024. Cortical hormones. SOC. OF CHEMICAL INDUSTRY IN BASLE. Dec. 23, 1937, Nos. 35623 and 35624. Convention dates, Dec. 23,1936 and Dec. 8, 1937. Samples furnished. [Class 2 (iii)] Compounds of the suprarenal cortical hormone series are prepared by treating compounds of the cortical hormone series with esterifying or etherifying agents, with the exception of those compounds which are designated as F.a, M, C and D in the publication in Helvetica Chemica Acta, Vol. 20, page 978, et seq. The esterification may be carried out with an acid, an anhydride, halide or ester thereof or with a ketene. Acids mentioned include acetic, chloracetic, propionic, butyric, isovaleric, succinic, palmitic, crotonic, benzoic, phenyl acetic, phosphoric, chlorsulphonic, carbamic or the monoalkoxy carbonic acids. The etherification is conducted in the usual manner and aryl aralkyl or alkyl residues may be introduced. Agents mentioned include triarylmethylhalides such as trityl chloride, diphenylhalogenated methane, nitrobenzylhalides, picryl chloride or the corresponding aryl-sulphonic ester. The esterification or etherification is preferably conducted in the presence of an acid binding agent such as pyridine dimethylaniline or a trialkylamine, or an alkali carbonate. It is stated that in the esterification or etherification processes the 21-hydroxyl group always enters into reaction. Under more energetic conditions, derivatives may be obtained of compounds of this series containing more than one-hydroxyl group or even of the enolic form of keto groups. The invention may be applied to the purification of compounds of the cortical hormone series by forming derivatives by the process of the invention, purifying the derivatives by distillation and then regenerating the starting material. Compounds which may be used as starting materials are characterized by a ketol grouping in the 17-position. Compounds specially named include #<4>-21-oxypregnene-dione-(3 : 20), #<4>-11 : 21-dioxy-pregnene-dione-(3 : 20), #<4>-11-keto-21-oxy-pregnene-dione-(3 : 20), and #<4>-17 : 21-dioxypregnane-dione-(3 : 20). In examples: (1) Cortico-sterone is treated with acetic anhydride in the presence of pyridine at room temperature for a long time to give corticosterone acetate. The same compound may also be made by the action of ketene,' or acetylhalides, on corticosterone. (2) Corticosterone is treated with butyric acid chloride in the presence of pyridine. Instead of the acid chloride, the corresponding acid anhydride may be used. In place of butyric acid there may be used, propionic, crotonic, valeric, caproic, oenanthic, caprylic, pelargonic, capric, lauric, myristic, or stearic acids. The reaction may be conducted in the presence of diluents of which there are mentioned ether, benzene, toluene and chloroform. In place of pyridine there may be used dimethylaniline, quinoline, a trialkylamine or an alkali carbonate. (3) Corticosterone is .treated with palmitic acid chloride in the presence of pyridine. (4) Suprarenal cortical hormone is treated under reflux with methyl butyrate in the presence of small amounts of sodium butyrate and potassium carbonate. Re-esterification may also be effected by altering the alcoholic groups, such as by using valerianic acid phenyl ester. (5) Corticosterone is treated with benzoyl chloride in the presence of pyridine. (6) Corticosterone is treated with succinic anhydride in the presence of pyridine. In place of succinic anhydride, other acylating compounds may be used which in addition to their acylating groups also contain a salt forming group such as phthalic anhydride, chlorosulphonic acid, chloracetic acid, bromopropionic acid or nitrobenzoic acid. (7) An acetone solution of desoxycorticosterone is treated with gaseous ketene to give desoxycorticosterone acetate. In a similar manner there may be obtained the acetate of 17-oxycorticosterone. (8) Trityl chloride is added to a pyridine solution of oily suprarenal cortical hormone to give a crystalline trityl compound. Similarly the cortical hormone in anhydrous triethylamine may be treated with dinitrobenzyl chloride to give the corresponding dinitrobenzyl ether. (9) Phosphorus oxychloride is dissolved in a pyridine solution of the cortical hormone, and after standing first on ice and then at room temperature the solution is poured into water and filtered. The filtrate on acidification gives the monophosphoric acid ester of the suprarenal cortical hormone. Samples have been furnished under Sect. 2 (5) of esters of desoxycorticosterone prepared in accordance with the following schedules: (1) Desoxycorticosterone in pyridine is treated with propionic anhydride to give desoxycorticosterone-propionate. (2) Desoxycorticosterone in pyridine is treated with butyric anhydride to give the corresponding desoxycorticosterone-nbutyrate. (3) Desoxycorticosterone is converted into its n-valerianate as in examples 1 and 2. (4) Desoxycorticosterone in pyridine solution is treated at freezing temperature with palmitic acid chloride to give the corresponding palmitate. (5) Desoxycorticosterone is treated in pyridine with benzoyl chloride to give the desoxycorticosterone benzoate.' (6) Desoxycorticosterone in pyridine is treated with stearic acid chloride in a cooling mixture, to give desoxycorticosterone stearate.