Patent GB-560811-A (GB)
Title: Manufacture of new compounds of the cyclopentanopolyhydrophenanthrene series
IPC: C07J9/00
Filed: 1942-03-20
Abstract: Compounds of the cyclopentanopolyhydrophenanthrene series which are unsaturated in ring C and which are substituted at least in ring A are prepared by treating a saturated or unsaturated compound of this series which is substituted in ring A and which contains in ring C a free or substituted hydroxyl group in the 12-position, with an agent which is known to be capable of splitting off such a substituent with the formation of a double bond.  Parent materials may, if desired, have a side chain in the 17-position and may be substituted outside ring A for example in positions 6, 7, or 17, or in the side chain for example in positions 20 or 21.  There are mentioned saturated and unsaturated androstane -3 : 12 : 12-triols, 3 : 12-diol-17-ones, and 3 : 17-dione-12-ols, the compounds may have in the 17-position in addition to a free or esterified hydroxyl group, a saturated or unsaturated hydrocarbon group, which may be substituted by alkyl alkenyl or alkinyl residues such as methyl, ethyl, diaryl-isopropyl, diaryl-isobutyl, diaryl-isoamyl, vinyl or ethinyl.  Other compounds are saturated or unsaturated pregnane-3 : 12-diole-20-ones, or 3 : 20-dione-12 oles, or 3 : 12-dioxy, 3 : 7 : 12-trioxy-, 3-keto-12-oxy, or 3 : 7-diketo-12-oxy cholanic acids and nor-, bisnor-, or aetio-cholanic acids.  As agents for the splitting off the hydroxyl group there are mentioned a mineral acid either alone or in solution in acetic acid, dioxane or alcohol solution, phosphoric acid, phosphorus oxychloride, or bisulphates also acid anhydrides such as acetic anhydride, and also catalysts such as iodides or salts of carboxylic acids. Esterified hydroxyl groups may be split off by alkalis, alkaline earths, carbonates, salts of carboxylic acids or organic bases such as pyridine and dimethylaniline.  A raised temperature and/or a reduced pressure may also be used, or the reaction may be conducted in the pressure of an inert gas.  In the case of hydrohalic esters the halogen may be exchanged for a quaternary ammonium residue instead of being split off directly.  In examples: (1) D 4,5-12-acetoxy-pregnene-3 : 20 dione is heated for 1-2 hours at 300 DEG  C. in nitrogen or under a reduced pressure to give D 4,5:11,12-pregnadiene-3 : 20-dione. Instead of the 12-acyloxyprogesterone there may be used compounds having an additional 21-acyloxy group.  (2) 3-Oxy-12-acetoxy-aetiocholanic acid is oxidized with chromic acid in glacial acetic acid to 3-keto-12-acetoxy-aetiocholanic acid and then distilled in a current of nitrogen under reduced pressure, esterified by diazomethane to produce D 11.12-3-keto-aetiocholanic acid methyl ester, which may be reduced to give the two stereoisomeric D 11.12-3-oxy-aetio-cholanic acid methyl esters.  The same final products are obtained when 3-keto-12-benzoxy-aetiocholanic acid methyl ester is decomposed by heat.  Similarly 12-acyloxy-aetiocholane 3 : 17-diones for example the 12-acetoxy compound can be converted into the corresponding D 11.12-aetiocholane-3 : 17-dione.  The same product is obtained by starting from diesters or mixed diesters of 3 : 12-dioxy-aetiocholane-17-one.  (3) 3-Keto-12-benzoxy-cholanic acid methyl ester is heated to 260 DEG  C. for 1/2 hour under 12 mm. pressure to give D 11.12-3-keto cholenic-acid methyl ester. From this compound two sterioisomeric D 11.12 - 3-oxy - cholenic acid methyl esters, are produced.  Instead of 3-keto-12-benzoxy cholanic acid methyl ester, other esters may be used, or the free acid itself.  In the latter case the fusion product obtained is D 11.12-3-keto cholenic acid.  (4) D 4.5 - 3 - keto - 12 - oxy cholenic acid is subjected to thermal scission as in example 3 to give D 4.5:11.12-3-keto choladienic acid.  (5) 3-Acetoxy-12-benzoxy cholanic acid methyl ester is subjected to thermal scission as described in example 3 to give D 11.12-3-acetoxy cholenic acid methyl ester. 3-Keto-12-benzoxy cholenic acid methyl ester is obtained by partially saponifying diacetyldesoxycholic acid methyl ester with 1 per cent methyl alcoholic hydrochloric acid to form 3-oxy-12-acetoxy-cholanic acid methyl ester followed by chromic acid oxidation to 3-keto-12-acetoxy cholanic acid methyl ester and energetic alkaline saponification to 3-keto-12-oxy-cholanic acid and finally esterification with methyl alcoholic hydrochloric acid.  D 4.5-3-Keto-12-oxycholenic acid is obtained from 3-keto-12-oxycholanic acid (prepared as above) by bromination, treatment with pyridine and subsequent saponification.  3-Acetoxy-12-benzoxy-cholanic acid methyl ester is obtained from desoxycholic acid methyl ester by partial esterification with acetic anhydride to form 3-acetoxy-12-oxycholanic acid methyl ester followed by benzoylation.  The Specification as open to inspection under Section 91 describes also the treatment according to the process of the invention of compounds which have instead of a free or substituted hydroxyl group, an amino group, for example a dialkylamine, trialkylammonium or pyridinium group.  When using compounds containing a free or substituted amino group it is preferred to work by way of the quaternary ammonium compounds.  This subject matter does not appear in the Specification as accepted.