GB461335A - Manufacture of polynuclear cyclic oxyketones and esters thereof - Google Patents

Manufacture of polynuclear cyclic oxyketones and esters thereof

Info

Publication number
GB461335A
GB461335A GB2325935A GB2325935A GB461335A GB 461335 A GB461335 A GB 461335A GB 2325935 A GB2325935 A GB 2325935A GB 2325935 A GB2325935 A GB 2325935A GB 461335 A GB461335 A GB 461335A
Authority
GB
United Kingdom
Prior art keywords
diol
androstane
acid
androstene
acetate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
GB2325935A
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
BASF Schweiz AG
Original Assignee
Gesellschaft fuer Chemische Industrie in Basel CIBA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gesellschaft fuer Chemische Industrie in Basel CIBA filed Critical Gesellschaft fuer Chemische Industrie in Basel CIBA
Priority to GB2325935A priority Critical patent/GB461335A/en
Publication of GB461335A publication Critical patent/GB461335A/en
Expired legal-status Critical Current

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Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J1/00Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07JSTEROIDS
    • C07J75/00Processes for the preparation of steroids in general

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Steroid Compounds (AREA)

Abstract

Polynuclear cyclic oxy-ketones of the saturated or unsaturated androstane series or esters thereof are prepared by the following methods: (1) a di-ester of a saturated or unsaturated androstane diol-(3 : 17) is partially saponified and the free carbinol group in the 3-position is then oxidized to a keto group, if necessary with intermediate protection of the nuclear double bond. The free oxy-ketone is then obtained from the ester by saponification; (2) a saturated or unsaturated androstane diol-(3 : 17) is partially esterified and the 17-mono ester so obtained is oxidized and then hydrolyzed as in (1) above; (3) a saturated or unsaturated androstane diol-(3 : 17) is subjected directly to partial oxidation if necessary with intermediate protection of the nuclear double bonds, and the 3-keto-17-ol-compound separated from the oxidation product. Among the androstane diols which are used as starting materials for the present invention are included those in which the 17-position is substituted by a hydrocarbon residue. In process (1) above it is preferred to use a mixed di-ester in which the hydroxyl group in the 3-position is esterified with an acid residue which is more easily saponifiable than that with which the hydroxyl group in the 17-position is esterified. Examples of such esters are those in which the 3-position is esterified with a lower fatty acid such as acetic acid or formic acid, and in the 17-position there is a higher fatty acid such as valeric acid, a carbamic acid, benzoic acid, hexahydrobenzoic acid or a hydrohalic acid. The partial saponification is preferably conducted by means of an alkaline agent in an organic solvent such as an aliphatic alcohol, dioxane or acetone. When an alcohol is used as solvent, a certain degree of rearrangement takes place and the theoretical amount of alkali is not always necessary. Suitable acylating agents for use when carrying out process (2) above are acids, such as benzoic acid, acetic acid, and formic acid, acid halides such as benzoyl chloride and acetyl chloride, and acid anhydrides such as acetic anhydride. It is preferred, particularly when using an acid halide or an acid anhydride to use only one equivalent of the acylating agent and to conduct the operation in the presence of an acid binding agent or an alkali. As suitable oxidizing agents for each of the three above methods, there may be used a hexavalent chromium compound, such as chromic acid in glacial acetic acid or copper oxide. In the case where an unsaturated diol is used it is preferred to protect the nuclear double bond by, for example, the addition of halogen or halogen hydride. The protecting agent, if a halogen, is removed after oxidation by treatment with zinc in glacial acetic acid or benzene, or with catalytically activated hydrogen, or with an alkali iodide. In the case of protection with halogen hydride, the protecting agent is removed by treatment with an alkaline agent such as a tertiary base. The carbinol group in the 3-position can also be converted into a keto group by the action of a dehydrogenating agent instead of by oxidation. As dehydrogenating agents, there may be used selenium, sulphur, or a metallic catalyst belonging to the group of hydrogenating or dehydrogenating catalysts such as copper, platinum, palladium, gold, and nickel. The reaction is preferably carried out in the presence of hydrogen acceptors such as naphthalene, quinoline, phenols, cinnamic acid, fumaric acid, cyclohexanone, benzophenone, quinones and aldehydes. The reaction may be carried out under reduced pressure or in the presence of inert gases. Dehydrogenation is preferred to oxidation on account of its greater simplicity and also by reason of the fact that intermediate protection of the nuclear double bond is not necessary. The oxy-ketones are isolated either by direct crystallization or by conversion into a derivative by reaction with ketone reagents such as semi-carbazide, thiosemicarbazide, hydroxylamine, aminoguanidine, phenylhydrazine and its substitution products, and neutral or basic acylhydrazides. In order to separate the 3-keto compound from any 3-oxy-compound which may have been formed as a by-product, a saponine such as digitonin is used when the steric arrangement of the hydroxyl group in the 3-position corresponds with that of cholesterol. Diols mentioned as suitable starting materials are the androstane diols-(3 : 17), the D <4 : 5> or D <5 : 6> -androstene diols-(3 : 17), the 17 - methyl or 17 - ethyl androstene diols-(3 : 17) in which in each case the carbinol groups in both 3- and 17-positions may be in cis- or epi, or in trans position. In examples: (1) androstane-diol-(3 : 17)-diacetate is hydrolyzed at room temperature with N/100 methyl alcoholic potash to give p 17-acetoxy androstane-ol-(3). The product is precipitated with water, dried, dissolved in glacial acetic acid and oxidized with chromium trioxide. The androstane-ol-(17)-one-(3) so produced is isolated by means of its semicarbazone, and purified by recrystallization from hexane. The propionate or butyrate may be used instead of the acetate; (2) D <5 : 6>-androstene-diol-(3 : 17)-diacetate is partially saponified at room temperature by alcoholic potassium hydroxide, the product isolated, and purified by recrystallization from hexane. Bromine is added to a glacial acetic acid solution to protect the nuclear double bond, followed by oxidation with chromic acid. When the oxidation is complete the bromine is removed by zinc dust and the D <4 : > 5-androstenol-(17)-one-(3)-acetate isolated by means of its semicarbazone. Saponification gives the free oxy-ketone. Other esters mentioned which may be used instead of the acetate as starting material are the benzoate, propionate, isobutyrate, n-valerianate, n-caprinate, palmitate, and stearate. The melting points of the oxy-ketones so obtained are given; (3) D <5 : > 6-3-trans-17-cis-androstene-diol-diacetate is hydrolyzed and oxidized with intermediate protection of the nuclear double bond as described in example (2) to give D <4 : > 5-androstene-cis-ol-(17)-one-(3). The starting material of this example is formed by acetylation of D <5 : > 6-3-trans-17-cis androstene-diol-3-acetate which is itself formed together with 3-trans-17-trans-diol-3-acetate by hydrogenation of D <5 : 6>-trans-dehydroandrosterone acetate; (4) D <5 : 6>-3-trans - androstene diol - 3 - acetate - 17 - benzoate is hydrolyzed and oxidized with intermediate protection of the nuclear double bond by bromine as described in example (2) except that the debromination is conducted by means of sodium iodide. The product is D <4 : > 5-androstene-trans-ol-(17)-one-(3)-benzoate. If the 17-cis compound is used as starting material there is obtained D <4 : > 5-androstene-cis-ol-(17)-one-(3). In this example, copper oxide may be used as the oxidizing agent instead of chromic acid; (5) D <5 : 6>-androstene-3 : 17-diol-3-acetate-17-benzoate is hydrolyzed in ethyl alcoholic solution and oxidized as in example (4) to give D <4 : 5>-androstene-3-one-17-ol-benzoate. Hydrolysis in ethyl alcohol is more rapid than in methyl alcohol. Propyl, amyl and butyl alcohols may also be used; (6) cis-androstane-diol-3-acetate-17-benzoate is hydrolyzed and oxidized as described in example (2) to give androstane-3-one-17-ol-benzoate. This compound may also be obtained by starting from trans-androstane-diol-3-acetate-17-benzoate; (7) androstane-diol-(3 : 17) is heated with glacial acetic acid for 8 hours on the water bath, the product precipitated with water and fractionally crystallized from benzine. From the more easily soluble fraction there is obtained the 17-monoacetate of androstane diol-(3 : 17). On oxidation as described in example (1) androstane-ol-(17)-one-(3) is obtained; (8) D <5 : > 6-andro-stane-diol-(3 : 17) is acetylated in pyridine solution with acetyl chloride and the D <5 : > 6-17-acetoxy-androstene-ol-(3) oxidized with intermediate protection of the double bond to give D <4 : > 5-androstene-ol-(17)-one-(3)-acetate. In a similar manner by partial benzoylation there may be obtained D <4 : > 5-androstene - ol - (17) - one - (3)-benzoate; (9) D <5 : > 6-androstene-3 : 17-diol-17- benzoate, obtainable as a by-product in examples 4, 5 and 7 is heated with copper powder in a vacuum to give D <4 : 5>-androstene-ol - (17) - one - (3) - benzoate. Instead of the benzoate the free diol may be used as starting material. Instead of copper another metal catalyst such as palladium, platinum or silver may be used for the dehydrogenation; (10) androstane 3 : 17-diol-17-acetate obtainable as an intermediate product in examples 1 and 6 is dissolved in glacial acetic acid together with an equal amount of cinnamic acid and shaken while warm with a palladium catalyst. The product consists of androstane-ol-(17)-one-(3) and is purified by conversion into its dinitrophenylhydrazine derivative. Instead of the mixture of cinnamic acid and androstane-diol-17-acetate there may be used an androstane 3 : 17-diol-17-cinnamic acid ester in which the hydroxyl group to be dehydrogenated and the hydrogen acceptor are united in the same molecule; (11) 17-methyl androstane diol-(3 : 17) is directly oxidized in glacial acetic acid solution with chromic acid to give 17-methyl-androstane-ol-(17)-one-(3) which is purified by its semicarbazone. In a similar manner, 17-ethyl-androstane-diol-(3 : 17) and 3-trans- or 3-cis-17-trans androstane diols may be treated to yield the corresponding oxy-ketone; (12) D <5 : > 6-17-methyl-androstene-diol-(3 : 17) is oxidized at room temperature with intermediate protection of the double bond to give D <4 : 5>-17-methyl androstene - ol - (17) - one - (3). D <5 : 6>-Androstene-diol-3 : 17 may be similarly treated. One may also start from compounds which are acylated in position 17 or otherwise substituted; (13) Androstane - 3 - trans - 17
GB2325935A 1935-08-19 1935-08-19 Manufacture of polynuclear cyclic oxyketones and esters thereof Expired GB461335A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
GB2325935A GB461335A (en) 1935-08-19 1935-08-19 Manufacture of polynuclear cyclic oxyketones and esters thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB2325935A GB461335A (en) 1935-08-19 1935-08-19 Manufacture of polynuclear cyclic oxyketones and esters thereof

Publications (1)

Publication Number Publication Date
GB461335A true GB461335A (en) 1937-02-15

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Family Applications (1)

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GB (1) GB461335A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2734066A (en) * 1956-02-07 Method for the preparation of dfflydro-

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2734066A (en) * 1956-02-07 Method for the preparation of dfflydro-

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