Patent GB-517078-A (GB)
Title: Manufacture of derivatives of the saturated and unsaturated cyclopentanopolyhydrophenanthrene series
IPC: C07J1/00
Filed: 1938-07-18
Abstract: 517,078. Cyclopentanophenanthrene alcohols. SOC. OF CHEMICAL INDUSTRY IN BASLE. July 18, 1938, Nos. 21252 and 21253. Convention dates, July 19, 1937, and June 22, 1938. [Class 2 (iii)] Secondary alcohols of the cyclopentanopolyhydrophenanthrene series are prepared from aldehydes of this series which contain the aldehyde group either at position -17 or separated by one carbon atom from the carbon atom -17, and which contain a nuclear keto group by treatment with an organic metal compound containing no organic radical with more than two carbon atoms. As organic metal compounds there may be used saturated or unsaturated compounds of metals such as alkali metals, magnesium, calcium or zinc, with substituted or unsubstituted methyl, ethyl, ethylene or acetylene residues ; also organic metal halides such as calcium, mercury, tin, magnesium, and zinc, methyl-, ethyl-, vinyl-, acetylene-, or methylether-halides. The parent material may contain nuclear substituents and particularly a tertiary hydroxyl-, acyloxy-, or alkoxy-group in the alpha position to the aldehyde group. In this case the secondary-tertiary glycol, or mono-substituted glycol thus produced may be treated to split off water, acid or alcohol. Mono-substituted glycols may have acid or alcohol split off directly, or the compound may be first saponified. The splitting off may be carried out by means of a mineral acid or an alkali, or by phosphorus oxychloride, a bisulphate, formic acid, oxalic acid, an acid anhydride or by the action of heat, preferably under reduced pressure or in an atmosphere of an indifferent gas. Ketones are thus obtained. If the parent materials do not contain such a substituent in the alpha position to the aldehyde group, the secondary alcohols which are produced by the process of the invertion may be converted into ketones by treatment with an oxidizing agent or a dehydrogenating agent such as chromic acid or a permanganate on one hand, or with a metal, a metal oxide or a metal alcoholate in presence of a carbonyl compound on the other hand. Nuclear double bonds are preferably protected during this oxidation by means, of halogen, and subsequently regenerated by treatment with zinc dust and acetic acid. In the case where organic magnesium halides are used as the metal organic compound, the nuclear keto groups are preferably protected by transformation into their enol esters or enol ethers, and reconverted after the main reaction has taken place. Instead of using an already prepared organic metal compound, there may be used to react on the aldehyde, the individual components of the compound, when the compound itself is unknown or unstable such as in the reaction of chloromethyl ether, or vinyl bromide with magnesium. When it is desired to use an alkyl alkali metal compound it is frequently advantageous to employ a hydrocarbon halide, or a hydrocarbon mercury compound together with sodium. In cases where the reaction results in the formation of addition compounds containing metal, the reaction mixture is worked up by treatment with a dilute acid. In examples (1) an ether solution of magnesium methyl iodide is added to an ether solution of the 3-enol acetate of #<4À5>-17- formyl-aetiocholene-3-one, and the reaction product decomposed by dilute sulphuric acid to give the crude 3-enol acetate of #<4À5>-pregnene- 3-one-20-ol. This is then saponified and oxidized by chromium trioxide in acetic acid to progesterone. Instead of the chromium trioxide as the oxidizing agent, there may be used heating with copper powder under reduced pressure, or with aluminium isopropylate or isobutylate and acetone. (2) the 3-enol acetate of #<4À5>-17- acetoxy-17-formyl-aetiocholene-3-one is treated with zinc dimethyl in ether solution, and worked up as in example (1) to give #<4À5>-pregnene- 17:20-diol-3-one: Water is now split off by treatment with hydrochloric acid in propyl alcohol solution to give progesterone. Instead of zinc dimethyl, there may be used methyl zinc iodide or ethyl magnesium bromide. In the latter case a homologue of progesterone is obtained. In a similar manner saturated compounds of the 3-epi-oxy-allopregnam series may be obtained. The Specification as open to inspection under Sect. 91 comprises also the use as parent materials for the invention in addition to aldehydes, carboxylic acids or carboxylic acid derivatives. The reactive group may be attached not only to position -17 but to any other position of the cyclopentanopolyhydrophenanthrene nucleus. The nucleus may not necessarily contain a keto group, and may contain other groups such as substituted or unsubstituted hydroxyl, carbinol amino or hydrocarbon groups and halogen atoms. Starting materials specified 3-oxy-, 3-keto-, and/or 17-oxy-aetio cholanic acids, also the aldehydes of bisnorcholanic acid, aetiocholanic-17-acetic acid, norcholanic acid cholanic acid, 3-carboxy-aetiocholane, as well as analogous acids of the oestrane and hydro-oestrane series. Compounds of the above series may be used which differ in stereochemical structure at the carbon atoms 3, 5, 9, 11, 12, 17 and/or 20. Compounds specified as suitable organo-metallic compounds included lithium-methyl, sodium-benzyl, phenyl-potassium, triphenylmethyl-sodium, acetylene-potassium, phenylacetylene-sodium, aluminium-triaskyls, and tin di- and -tetra-alkyls. An example was furnished in which the starting material was A <5À6>-3 oxy-17-formyl-aetiocholene, and in which the treatment was as described in example (1) above. This subject-matter does not appear in the Specification as accepted.