Patent GB-435563-A (GB)
Title: Manufacture of polynuclear cyclic ketones
IPC: C07J75/00
Filed: 1934-03-24
Abstract: Polynuclear substituted cyclic ketones are prepared from sterols and bile acids containing saturated nuclei or from derivatives or partial degradation products thereof by a process which comprises (1) oxidizing derivatives of the parent materials in which the hydroxyl group or groups have been protected from oxidation by substitution; (2) separating the neutral portion of the oxidation product; (3) isolating the required cyclic ketones from the non-volatile neutral portion; and (optionally) (4) removing the protecting group to produce hydroxy substituted cyclic ketones.  Suitable oxidizing agents are chromic acid and permanganate.  The preferred treatment of the neutral fraction comprises: (1) Removal of the volatile neutral constituents by steam or by heating in a vacuum.  (2) Removal of unchanged parent material by extraction with a solvent such as cold methyl or ethyl alcohol, whereby the bulk of the parent material remains undissolved.  (3) Isolation of the cyclic ketone by means of a ketone reagent followed by regeneration from the ketone derivative. Suitable ketone reagents mentioned are semi-carbazide, hydroxylamine, phenyl-hydrazine, diphenylhydrazine, mono- or di-nitrophenylhydrazine, and phenylhydrazine sulphonic acid.  The decomposition of the double compound formed from the cyclic ketone and the ketone reagent may take place under energetic conditions, for instance by alternate saponification with an acid and with caustic alkali, or by treatment with 1 : 1-sulphuric acid, in which case complete hydrolysis takes place with the production of the hydroxyketone. Alternatively, mild hydrolysis conditions may be employed to yield the ketone ester, by splitting off only the ketone reagent. Suitable mild conditions are obtained by the use of an acid agent in the presence of a small proportion of water, and in the presence of an organic solvent, for example, glacial acetic acid. The esters so produced are stated to have a more prolonged physiological action than the hydroxyketones themselves.  In examples: (1) Dihydrocholesteryl chloride is oxidized in glacial acetic acid solution with chromic acid, and the chlor-ketone resulting is separated from the non-volatile neutral oxidation product using semicarbazide as the ketone reagent.  The corresponding bromo- or iodo-ketones may be obtained by oxidation of dihydrocholesteryl bromide or iodide.  (2) Dihydrocholesteryl acetate is oxidized in glacial acetic acid solution with chromic acid and the semi-carbazide C22H3O35N3 of the keto-acetate C21H32O3 is isolated.  On vigorous hydrolysis using equal parts of concentrated hydrochloric acid and glacial acetic acid followed by boiling with alcoholic caustic soda a hydroxy ketone m.p. 174--175 DEG  C. is isolated.  (3) Epi-dihydrocholesteryl acetate is oxidized and worked up as described in example (2) to yield a hydroxy ketone m.p. 183 DEG  C. (4) The oxidation in examples (2) or (3) is carried out with potassium permanganate instead of chromic acid.  (5) Dihydro-sitosteryl acetate is treated as described in examples (1) and (2) to yield the same hydroxy ketone as described in example (2).  (6) Coprosteryl acetate is treated as described in examples (1) and (2) to yield a hydroxy ketone of m.p. 151--152 DEG  C.  (7) Epi-coprosteryl acetate when treated as above described yields a hydroxyketone m.p. 151--152 DEG C.  (8) Lithocholic ester is converted into the corresponding diol by a large excess of sodium in absolute alcohol solution, the diol treated with acetic anhydride, and the diacetate oxidized with chromic acid and worked up as described in example (1).  A hydroxy ketone was isolated identical with that prepared from epi-coprosteryl acetate in example (7).  (9) Acetyl-lithocholic ester is oxidized as described in example (1), to yield the same hydroxyketone as obtained in examples (7) and (8).  (10) The semicarbazone of the acetate of the hydroxyketone resulting from the oxidation of the acetate of epi-dihydrocholesterin is submitted to a gentle hydrolysis to yield the acetate of the hydroxy ketone m.p. 164--165 DEG  C.  (11) The semicarbazone of the benzoate of the hydroxyketone resulting from the oxidation of the benzoate of dihydrocholesterin is gently hydrolyzed to yield the benzoate of the hydroxyketone m.p. 174--175 DEG C.ALSO:Polynuclear substituted cyclic ketones related to the sexual hormones are prepared from sterols and bile acids containing saturated nuclei or from derivatives or partial degradation products thereof by a process which comprises (1) oxidizing derivatives of the parent materials in which the hydroxyl group or groups have been protected from oxidation by substitution; (2) separating the neutral portion of the oxidation product; (3) isolating the required cyclic ketones from the non-volatile neutral portion; and (optionally) (4) removing the protecting group to produce hydroxy substituted cyclic ketones.  Suitable oxidizing agents are chromic acid and permanganate.  The preferred treatment of the neutral fraction comprises: (1) Removal of the volatile neutral constituents by steam or by heating in a vacuum. (2) Removal of unchanged parent material by extraction with a solvent such as cold methyl or ethyl alcohol, whereby the bulk of the parent material remains undissolved.  (3) Isolation of the cyclic ketone by means of a ketone reagent followed by regeneration from the ketone derivative.  Suitable ketone reagents mentioned are semicarbazide, hydroxylamine, phenyl-hydrazine, diphenylhydrazine, mono- or di-nitrophenyl-hydrazine, and phenylhydrazine sulphonic acid.  The decomposition of the double compound formed from the cyclic ketone and the ketone reagent may take place under energetic conditions, for instance by alternate saponification with an acid and with caustic alkali, or by treatment with 1 : 1-sulphuric acid, in which case complete hydrolysis takes place with the production of the hydroxyketone. Alternatively, mild hydrolysis conditions may be employed to yield the ketone ester, by splitting off only the ketone reagent. Suitable mild conditions are obtained by the use of an acid agent in the presence of a small proportion of water, and in the presence of an organic solvent, for example, glacial acetic acid. The esters so produced are stated to have a more prolonged physiological action then the hydroxyketones themselves.  In examples: (1) Dihydrochlolesteryl chloride is oxidized in glacial acetic acid solution with chromic acid, and the chlor-ketone resulting is separated from the non-volatile neutral oxidation product using semicarbazide as the ketone reagent.  The corresponding bromo- or iodo-ketones may be obtained by oxidation of dihydrocholesteryl bromide or iodide.  (2) Dihydrocholesteryl acetate is oxidized in glacial acetic acid solution with chromic acid and the semicarbazide C22H3O35N5 of the keto-acetate C21H32O3 is isolated. On vigorous hydrolysis using equal parts of concentrated hydrochloric acid and glacial acetic acid followed by boiling with alcoholic caustic soda a hydroxy ketone m.p. 174-175 DEG  C. is isolated.  (3) Epi-dihydrocholesteryl acetate is oxidized and worked up as described in example (2) to yield a hydroxy ketone m.p. 183 DEG  C. (4) The oxidation in examples (2) or (3) is carried out with potassium permanganate instead of chromic acid.  (5) Dihydro-sitosteryl acetate is treated as described in examples (1) and (2) to yield the same hydroxy ketone as described in example (2).  (6) Coprosteryl acetate is treated as described in examples (1) and (2) to yield a hydroxy ketone of m.p. 151 DEG -152 DEG  C.  (7) Epi-coprosteryl acetate when treated as above described yields a hydroxyketone m.p. 151-152 DEG C.  (8) Lithocholic ester is converted into the corresponding diol by a large excess of sodium in absolute alcohol solution, the diol treated with acetic anhydride, and the diacetate oxidized with chromic acid and worked up as described in example (1).  A hydroxy ketone was isolated identical with that prepared from epi-coprosteryl acetate in example (7).  (9) Acetyl-lithocholic ester is oxidized as described in example (1), to yield the same hydroxyketone as obtained in examples (7) and (8).  (10) The semicarbazone of the acetate of the hydroxyketone resulting from the oxidation of the acetate of epi-dihydrocholesterin is submitted to a gentle hydrolysis to yield the acetate of the hydroxy ketone m.p. 164-165 DEG  C.  (11) The semicarbazone of the benzoate of the hydroxyketone resulting from the oxidation of the benzoate of dihydrocholesterin is gently hydrolyzed to yield the benzoate of the hydroxyketone m.p. 174-175 DEG  C. p