Patent GB-552047-A (GB)
Title: Process for making pseudo-sapogenin compounds and derivatives thereof
IPC: C07J5/00
Filed: 1941-02-04
Abstract: 552,047. Pseudo-sapogenin compounds. PARKE, DAVIS & CO. Feb. 4, 1941, No. 1495. Convention date, Feb. 5, 1940. [Class 2 (iii)] Steroidal sapogenin derivatives which are known as pseudo-genin compounds are prepared by a process of isomerizing and acylating a steroidal sapogenin which comprises reacting the steroidal sapogenin with an acylating agent above 150‹C. The compounds so produced are not identical with the products obtained by acylating a steroidal sapogenin under normal acylating conditions. The preferred acylating agents are lower fatty acid anhydrides but a mixture of benzoyl chloride and sodium acetate may also be used. Steroidal sapogenins which may be used as starting materials include not only the aglycones of the naturally occurring steroidal sapogenins but also their derivatives formed by changes in Rings A or B provided the side chain on ring -D remains intact. Compounds mentioned include smilagenin, sarsasapogenone, 3-desoxysarsasapogenin, and the sarsasapogenyl chlorides. Sarsasapogenin is however specifically excluded from the process of the present invention. The pseudo-genins formed according to' the present invention differ from the naturally occurring sapogenins in having  ' a reactive or acylatable hydroxyl in the grouping attached to ring -D. The pseudogenins or their acylated or side-chain hydrogenated derivatives may be oxidized to form etio-bilianic acids and C 2o -oxygenated pregnane derivatives which are not obtained when sapogenins are oxidized. The pseudo genins under mild oxidizing conditions, e.g. with chromic acid in acetic acid at room temperature, give mainly #<SP>16</SP>-unsaturated-20-keto-pregnane derivatives, and a small amount of etiobilianic acid. Under more vigorous conditions, the etio-bilianic acid is the major product. Oxidizing agents mentioned include potassium permanganate, in acetic acid, chromium trioxide in acetic anhydride, potassium bichromate and sulphuric acid in aqueous acetone, and nitric acid. The #<SP>16</SP>-20-keto-pregnane derivatives may be reduced with the formation of 20-keto or 20-hydroxy-pregnane derivatives. The 20-keto-pregnane compounds result from the use of mild agents such as hydrogen in the presence of a palladium catalyst, while the 20-hydroxy-pregnane compounds result from more vigorous agents such as sodium and alcohol or catalytic reduction using Adam's platinum oxide catalyst. In examples (1) Sarsasapogenone prepared by oxidation in acetic acid solution with chromic anhydride of sarsasapogenin is heated in a bomb tube with acetic anhydride at 200 ‹C. for 10 hours to give pseudo sarsasapogenone. Oxidation of this compound with chromic anhydride in acetic acid gives #<SP>16</SP>-pregnenedione-3:20, which can be reduced with hydrogen in the presence of a palladium barium sulphate catalyst to pregnanedione-3:20. Reduction of the #<SP>16</SP>-pregnanedione-3:20 in alcohol solution with hydrogen in the presence of Adams' platinum oxide catalyst gives pregnanediol-3-(α)-20-(#) and pregnanediol-3-(#)-20-(#) which are separated by digitonin. (2) Chlorogenin is treated with acetic anhydride at 200‹C. for 10 hours to give pseudo-chlorogenin which on oxidation with chromic anhydride in acetic acid forms #<SP>16</SP>- allo-pregnenetrione-3:6:20. This compound on reduction with Adams' platinum oxide catalyst gives allo-pregnanetriol-3:6:20. Oxidation of this with chromic anhydride in acetic acid forms allo-pregnanetrione-3:6:20. (3) Tigogenin is heated with n-caproic anhydride at 220‹C. for 8 hours to form pseudo-tigogenin, which on oxidation with concentrated sulphuric acid and sodium dichromate forms #<SP>16</SP>-allo pregnenedione-3:20. Reduction of this with hydrogen in the presence of a barium sulphate palladium catalyst forms allo-pregnanedione-3:20. (4) Diosgenin is treated with benzoyl chloride and freshly fused sodium acetate at 220‹C. for 10 hours to form pseudo-diosgenin which on oxidation with potassium permanganate in the presence of concentrated sulphuric acid forms #<SP>4, 16</SP>, <SP>4</SP>-pregnadiene-trione-3:6:20. This compound on reduction with zinc dust and acetic acid forms allo-pregnanetrione-3:6:20. (5) Gitogenin is heated in a bomb tube with acetic anhydride for 10 hours to form pseudo-gitogenin which on oxidation with nitric acid forms etio-bilianic acid. Pseudo-gitogenin on acetylation followed by oxidation with chromic anhydride in acetic acid gives #<SP>16</SP>-allo-pregnenone-20-diol-2:3-diacetate. (7) A solution of pseudo-chlorogenin prepared as in example 2 is reduced by hydrogen in the presence of platinum oxide catalyst in acetic acid solution to form dihydro-pseudo-chlorogenin. This compound on acetylation with acetic anhydride forms dihydro-pseudo-chlorogenin-triacetate which on oxidation followed by hydrolysis gives #<SP>16</SP>allo-pregnenone-20-diol-3:6. Hydrogenation in the presence of a palladium on barium sulphate catalyst forms allo-pregnanone- 20-diol-3:6. The Specification as open to inspection under Sect. 91 includes also the treatment of the genin sarsasapogenin. The following examples are also included : (1) Sarsasapogenin acetate is treated with acetic anhydride at 195‹-200‹C. for 10 hours to form pseudo-sarsasapogenin which is separated and purified in the form of its di-p-nitrobenzoate. Pseudo-sarsasapogenin is converted into its diacetate by treatment with acetic anhydride, and then oxidized with chromic anhydride in acetic acid to give 3-(#)-hydroxyetio-bilianic acid. (2) Sarsasapogenin is treated with propionic anhydride at 195-200‹C. for 10 hours to form pseudosarsasapogenin. Oxidation of this with chromic anhydride in acetic acid gives #<SP>16</SP>-pregnenedione-3:20, together with a small amount of 3-keto-etio-bilianic acid. #<SP>16</SP>-pregnenedione-3:20 on reduction with sodium in alcohol forms pregnanediol-3 (α)- 20 (α). (3) Sarsasapogenin is refluxed with n-butyric anhydride for 8 hours to form pseudosarsasapogenin, which after conversion into the di-acetate is oxidized with chromic anhydride to 3-(#)-hydroxy-etio-bilianic acid. There is also obtained some #<SP>16</SP>-pregnenone 20-ol-3 (#), which on reduction with sodium in alcohol forms pregnanediol-3 (#)-20-(α). (4) Sarsasapogenin acetate is treated with succinic anhydride for 10 hours at 195-200‹C. to form pseudo-sarsasapogenin, which on reduction with Adams' platinum oxide catalyst to give exo-dihydro-pseudo-sarsasapogenin. This is characterized by the formation of its bis-pnitrobenzoate. Oxidation of exo-dihydropseudo-sarsasapogenin with chromic anhydride forms #<SP>16</SP>-pregnenedione-3:20, which on reduction with palladium barium sulphate ca,talyst forms pregnene-dione-3:20. (5) Exodihydro-pseudo-sarsasapogenin is acetylated with acetic anhydride, and the diacetate thus formed is oxidized with chromic anhydride to 3-(#)-hydroxy-etio-bilianic acid. Under milder conditions of oxidation the main product is #<SP>16</SP>-pregnenone-20-ol-3 (#) acetate. (6) #<SP>16</SP>- pregnenol-3 (#)-one 20 prepared as above is reduced in presence of Adams' platinum oxide catalyst to pregnenediol-3:20. Oxidation of #<SP>16</SP>-pregnenol-3-#-one-20 without preliminary reduction results in #<SP>16</SP>-pregnenedione- 3:20. (7) The #<SP>16</SP> unsaturated-20-keto pregnane derivatives may be reduced by a variety of methods of which there are specified catalytic reduction in the presence of a noble metal catalyst such as platinum or palladium, or reduction by metals more electro positive than hydrogen in the presence of substances having reactive hydroxyl groups such as water, alcohols or bases. This subject-matter does not appear in the Specification as accepted.