Patent GB-550478-A (GB)
Title: Manufacture of oxidation products of the dimethylcyclopentanopolyhydrophenanthrene series
IPC: C07J75/00
Filed: 1940-12-18
Abstract: 550,478. Oxidation of cyclopentano-polyhydrophenanthrene compounds. SOC. OF CHEMICAL INDUSTRY IN BASLE. Dec. 18, 1940, Nos. 17837 and 17838. Convention dates, Dec. 19, 1939 and March 12, 1940. [Class 2 (iii)] Oxo-compounds or carboxylic acids of the dimethyl - cyclopentanopolyhydrophenanthrene series are prepared by treating a compound of this series containing a side chain in 17-position and containing in 5-position a free or esterified or etherified tertiary hydroxyl group but no other nuclear substituent, or a corresponding unsaturated compound obtainable therefrom by splitting off the hydroxyl group, with an oxidizing agent known to be capable of bringing about side chain degradation. The non- volatile products of the oxidation which are formed by partial or complete oxidation of the side chain are separated from the reaction mixture. If desired the nuclear double links may be protected during the oxidation in which case the protecting agent is later removed. The preferred method of separation of the desired reaction products is to remove first the carboxylic acids, and then to recover and separate the oxo-compounds by means of a ketone reagent or by fractional crystallization, absorption, or sublimation in vacuo. The carboxylic acids may be separated from one another by fractional esterification and/or fractional saponification of the esters obtained. When the parent materials comprise compounds in which there is a free or esterified or etherified hydroxyl group in 5-position, the oxidation product may be treated with an agent which eliminates water acid or alcohol to form a nuclear double linkage in the 4 : 5-, or 5 : 6-position. When the parent materials comprise compounds which contain a nuclear double link, and when also this double link is not protected, there are obtained poly-carbonyl compounds by the introduction of a keto group into the α-position to the double linkage. The oxidation mixture in this contains both neutral degradation products containing one or two keto groups in the nucleus and/or in the side chain, and also acid degradation products which may or may 'not contain a keto group in the nucleus. Parent materials mentioned include # <SP>4</SP>-, and #<SP>5</SP>- cholestene, #<SP>4</SP>-, and #<SP>5</SP>-sitostene, # <SP>5</SP> : <SP>6</SP>, <SP>22</SP> : <SP>23</SP>-, stigmastadiene and #<SP>5</SP>- allocholenic acid, also cholestane - 5 - ol, coprostane - 5 - ol, sitostane - 5 - ol, and 5 - oxy - cholanic acid, each of which is obtainable from the corresponding unsaturated compound by oxidation with perbenzoic acid and catalytic reduction of the resulting 4: 5 -, or 5 : 6-oxido compound. In addition esters of the above 5 'hydroxy compounds may be used particularly esters with hydro-halogen acids. The #<SP>4</SP>-, or #<SP>5</SP>- compounds are obtainable from the 5 - hydroxy compounds by splitting off water, and the former are also obtainable by heating #<SP>4</SP> - 3 - ketones with sodium ethylate. Mixtures of sterols and like acids may also be used which contain the above described nuclear double linkages or tertiary hydroxyl group. Oxidizing agents mentioned include chromic acid, a permanganate, a peroxide, and a lead tetra-acylate. The oxidation may also be carried out electrolytically or by means of oxygen in the presence of an oxygen carrier such as lead peroxide or vanadic acid. Oxidation catalysts such as a halogen, or a strong inorganic acid such as sulphuric or perchloric acid may be added. Agents which may be used for the protection of the nuclear double links include halogen and halogen hydride. The protecting agent may be removed by means of zinc dust and acetic acid, zinc dust and methanol, an alkali iodide or catalytically active hydrogen, also tertiary bases such as pyridine or dimethylaniline and salts of carboxylic acids and alkalis. The separation of the carbonyl compounds is preferably carried out by means of ketone reagents, several of which are specified. When an unsaturated compound such as cholestene is used as the parent material, and the double linkages are protected, there are obtained unsaturated compounds such as androstene- 17-ones, pregnene - 20 - ones, nor-cholestene -25- ones, norcholestene - 20 - ones, cholenic acids, nor - cholenic acids, bisnor - cholenic acids and etio-cholenic acids. When the oxidation is carried out without protection of the nuclear double links there are obtained the corresponding diketones and keto-carboxylic acids such as androstenediones, pregnenediones and ketoetio-cholenic acids. When compounds containing the tertiary hydroxyl group are used as starting materials or substituted hydroxyl groups such as cholestane - 5 - ol, 5 - chloro-, or 5 - bromo - cholestane, there are obtained corresponding reaction products of the androstane, pregnane, norcholestane, bisnorcholane aldehyde, cholanic acid or etiocholanic acid series. In examples (1) a glacial acetic acid solution of 5 - chlorocholestane is treated with chromium trioxide in acetic acid solution at 20‹C. The excess of oxidizing agent is removed and the acid reaction products separated by treatment with alkali carbonate. There are thus obtained 5 - chlorocholanic acid and 5 - chloro-etio-cholanic acid which are separated by crystallization. The carbonyl, compounds are separated by treatment with pyridinium acetic acid hydrazide, and are then separated from one another by a fractional decomposition of the carbonyl addition compounds. There are thus obtained 5 - chloro - androstane - 17 - one, 5 - chloro - pregnane - 20 - one, 5 - chloro - norcholestane - 20 - one, and 5 - chloro - norcholestane - 25 - one. Alternative starting materials mentioned are 5 - chlorositostane and 5 - chloro - stigmastene, also 5 - oxy - cholestane. (2) The nuclear double bond of #<SP>4</SP>- cholestane is protected by the addition of bromine and the resulting 4 : 5- dibromocholestane oxidized in glacial acetic acid solution bv chromium trioxide. The oxidation product is worked up as in example (1) and from the acid portion there are isolated # <SP>4</SP>- cholenic acid, # <SP>4</SP> norcholenic acid, # <SP>4</SP>- bisnorcholenic acid, and #<SP>4</SP>- etiocholenic acid. From the carbonyl portion there are isolated #<SP>4</SP>- androstene - 17 - one, #<SP>4</SP> pregnane - 20 - one, #<SP>4</SP>- cholestene - 20 - one and # <SP>4</SP>-cholestene- 25 - one. The same final products are obtained if dibromositostene, or dibromostigmastadiene are used as the parent material. (3) #<SP>4-</SP> cholestene is oxidized with chromic acid as described in example (2) but without protection of the double linkage. There are obtained 3 - keto - cholenic acid and 3 - keto etio - cholenic acid. From the carbonyl portion there are isolated # <SP>4</SP>-androstenedione, #<SP>4</SP>- pregnenedione, #<SP>4</SP> 3 : 20 - cholestendione, and #<SP>4</SP>- cholestene- 3 : 25 - dione. The Specification as open to inspection under Sect. 91 included as starting materials quite generally compounds of the dimethyl - cyclopentanopolyhydrophenanthrene series containing any desired side chain in the 17- position and also containing in the ring A or B in any position double linkages or tertiary hydroxyl groups. The oxidizing agents which might be used were undefined in character. Compounds mentioned include #<SP>1</SP>-, #<SP>2</SP>-, #<SP>3-</SP>, # <SP>4</SP>-, and #<SP>5</SP>- cholestenes, -coprostenes, -sitostenes, stigmastadienes, and cholenic' acids, 5 - oxycholenic acids together with derivatives, homologues and conversion products of these compounds. This subject-matter does not appear in the Specification as accepted.