Patent GB-531177-A (GB)
Title: Manufacture of aldehydes of the saturated and unsaturated pregnane series
IPC: C07J5/00
Filed: 1939-06-28
Abstract: 531,177. Aldehydes of the pregnane series. SOC. OF CHEMICAL INDUSTRY IN BASLE. June 28, 1939, Nos. 18805, 18806, 18807 and 18808. Convention dates, July 1, 1938, Nov. 14, 1938, May 12, 1939, and June 13, 1939. [Class 2 (iii)] Aldehydes of the saturated or unsaturated pregnane series are obtained by (1) Oxidizing a 21-oxy compound of the pregnane series or an inorganic ester or a sulphonic acid ester thereof. (2) Reducing a 21-acid derivative of the pregnane series. (3) Splitting by oxidation or hydrolysis a compound of the pregnane series which has a side chain double linking in the 21-position. As exidixing agents in modification (1) above, there may be used 'the usual known agents for converting an oxy group into an aldehyde group. In addition, there may also be used the exchange of oxidation stages with carboxyl compounds in the presence of metal alcoholates, bio-chemical oxidation, treatment of a 21-halogen cr a 21-toluene sulphonic acid ester with hexamethylenetetramine or with a nitroso compound. The formation of the nitrone by the last mentioned method is particularly suitable where the parent material is a 21-halogen compound with an active hydrogen atom in the 21-position such as a #<SP>17,20</SP>-21-halogen compound or a 20-keto-21- halogen compound. Other oxidizable groups present are simultaneously oxidized, but if this is not desired such other groups may be protected. Nuclear double links may also be protected if their attack is not desired, as 21-acid materials suitable for treatment under modification (2) of the present invention there are mentioned carboxylic acid halides or anhydrid s, a carboxylic acid salt, an imido halide and a diarylamine. Reduction methods used are those which are normally employed to effect the reduction of a carboxylic acid group to an aldehyde group. If the parent material should contain an ethylene oxide group in the 17:20-position this will be simultaneously reduced with the formation of a hydroxyl group. The third alternative method of carrying out the present invention consists in splitting double links in the side chain, which may be either carbon-carbon double links or carbon-nitrogen double links. In the former case it may be done by ozonizing and splitting the ozonide by the action of a peroxide preferably in the presence of osmium tetroxide, or by adding two hydroxyl groups at the double linking and the scission of the glycol thus produced. In the case of carbon-nitrogen double bands the splitting may be done hydrolylically. Nuclear double bonds may be protected if desired. The parent material may contain nuclear substituents as well as side chain substituents. Compounds mentioned include in addition to 17:20 unsaturated compounds, also compounds in which this position contains an oxido group or one or two free or substituted hydroxyl groups such as acyloxy, alkoxy, or halogen group or a methylene group or a keto group in the 20-position. At any stage in the process a hydroxyl group in the 17-position may be eliminated as water. The compounds of the present invention may be treated to introduce a free or substituted hydroxyl group in the alpha position to the new aldehyde group, and the compound thus obtained may be treated with a re-esterifying, hydrolysing, and/or esterifying cr etberifying agent. For this purpose the compound may be attached by halogen and the α-halogen compound so obtained converted to a free or substituted hydroxyl group by treatment with a hydrolysing or re-esterifying agent. The same result may also be attained by adding an oxygen to the aldehyde enol derivative of the parent material and treating the ethylene oxide compound thus obtained with a hydrolyzing agent, or by saturating the enol double linking with free esterified or etherified hydroxyl groups. In examples: (1) Chromic acid in acetic acid solution is added to a benzene-glacial acetic solution of #<SP>4À5:17À20</SP>-pregnadiene-3-one- 21-ol, and the mixture heated to 60‹-70‹C. There is obtained on working up #<SP>45:17À20-</SP> pregnadiene-3-one-21-al. (2) A glacial acetic acid solution of #<SP>5À6-17</SP>-alkyl-androsrene-3:17- diol-3 monoacetate is ozonized after protection of nuclear double bonds by means of bromine. After dehalogenation by.zinc dust and extraction of the carbonyl compound by reaction with trimethylaminoacetic acid bydrazide there is obtained on working up the extract #<SP>5À6:17À20</SP>3- acetoxy-pregnadiene-21-al. Instead of ozonizing the brominated starting material, two hydroxyl groups may be added to the side chain double linking by means of osmium tetroxide, and from the tetrol thus produced there may be obtained by the action of periodic acid or lead tetracetate the #<SP>5À6</SP>-pregnene-3:17-diol-21-al aid its 3-monoacetate or by eliminating water the described #<SP>5À6:17À20</SP>-3 acetoxy-pregnadiene- 21-al. Similarly <SP>#4À5</SP>-pregnene-3-one-17-ol-21- al may be obtained from #<SP>5À6</SP>-17-Allyl-androstene-3-one-17-ol. (3) 3-acetoxy-androstane- 17-acetic acid chloride is reduced in xylene solution with hydrogen in the presence of a palladium-barium sulphate catalyst to give 3 - acetoxy - pregnane - 21 - al. An alternative starting material is the corresponding 17 20- oxido compound, in which case the oxygen bridge is also reduced. From the 3-acetoxypregnane-21-al there is obtained by bromination and re-esterification the 3 20-diacetoxy-pregnane-21-al, which gives the corresponding diol on hydrolysis. (4) #<SP>4.5</SP> - pregnene - 3 : 20 - dione-21-ol is converted by treatment with phenylhydrazine in acetic acid solution into phenyloxazone-phenylhydrazone, and this on decomposition with hydrochloric acid gives #<SP>4À5</SP> - pregnene - 3 : 20 - dione - 21 - al. (5) # <SP>5À6</SP> - pregnene - 3 : 17 : 20 : 21 - tetrol on treatment with aluminium isopropylate and benzaldehyde gives #<SP>4À5</SP> - pregnene - 3 : 20 - dione - 17 - ol - 21 - al. A ketone may be used instead of the benzaldehyde. (6) # <SP>4À5</SP>-pregnene- 17 : 20 : 21-triol-3-one is oxidized with hydrogen peroxide in aqueous dioxane solution to give #<SP>4À5</SP>- pregnene - 17 : 20 - diol - 3 - one - 21 - al. As an alternative starting material there may be used the 20-mono-, or 17:20-diacyl compound. (7) #<SP>4À5</SP> - 21 - bromo - pregnene - 3 - one is heated with hexamethylene tetramine to give # <SP>4À5</SP>-pregnene-3-one-21-al. This on treatment with sodium acetate and acetic anhydride is converted into its 21-enol acetate. The Specification as open to inspection under Sect. 91 includes an additional example in which #<SP>4:5:17:20</SP>-21 bromo - pregnadiene - 3-one is boiled with pyridine and the pyridinium bromide treated with nitroso-benzene to give #<SP>4 :</SP> <SP>5:</SP> <SP>17: </SP><SP>20</SP> - pregnadiene - 3 - one - 21 - al. Quinoline or dimethylaniline may be used instead of pyridine, and paranitrosodimethylaniline may be used instead of nitroso-benzene. This subject-matter does not appear in the Specification as accepted.