Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J21/00—Normal steroids containing carbon, hydrogen, halogen or oxygen having an oxygen-containing hetero ring spiro-condensed with the cyclopenta(a)hydrophenanthrene skeleton
  • C07J21/001—Lactones
  • C07J21/003—Lactones at position 17
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
  • C07J1/0003—Androstane derivatives
  • C07J1/0018—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa
  • C07J1/0022—Androstane derivatives substituted in position 17 beta, not substituted in position 17 alfa the substituent being an OH group free esterified or etherified
  • C07J1/0025—Esters
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
  • C07J53/002—Carbocyclic rings fused
  • C07J53/004—3 membered carbocyclic rings
  • C07J53/008—3 membered carbocyclic rings in position 15/16
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07J—STEROIDS
  • C07J71/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring
  • C07J71/0005—Oxygen-containing hetero ring
  • C07J71/001—Oxiranes

Definitions

• the invention relates to the subject matter of the claims.
• Acyl is understood to mean those acid residues which have up to 12 C atoms and are derived from acids which are usually used in steroid chemistry
• Preferred acids are carboxylic acids with 1 to 8 carbon atoms.
• the carboxylic acids can also be branched, polybasic or substituted in a conventional manner, for example by a hydroxyl or an amino group. Cycloaliphatic, aromatic, mixed aromatic aliphatic or heterocyclic acids are also suitable. Examples of preferred acids for forming the acyl radical are acetic acid, propionic acid, capronic acid, trimethylacetic acid, cyclopentylpropionic acid,
• Cyclohexylacetic acid phenylpropionic acid, phenylacetic acid, dialkylaminoacetic acid, piperidinoacetic acid, succinic acid and benzoic acid.
• Alkyl is to be understood as those radicals which are derived from aliphatic hydrocarbons and have 1 to 6 C atoms, such as Methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl and tert-butyl.
• the compounds which can be prepared according to the invention are intermediate products for the preparation of 3-keto- ⁇ 4 -6ß.7 ⁇ -methylene steroids which are pharmacologically valuable substances.
• 3 ⁇ -acetoxy-5-hydroxy-5ß.17 ⁇ -pregn-6-en-21.17-carbolactone can be obtained from 3ß-acetoxy-5.6ß-epoxy-5ß-pregnan-21.17-carbolactone via the intermediate stage of 3ß- Acetoxy-5-hydroxy-6 ⁇ -phenylseleno-5ß-pregnan-17.21-carbolactone can be produced (Helv.Chim. Acta 62 (1976) 2276).
• the process according to the invention is carried out in such a way that the 7 ⁇ -chloro-5ß.6ß-epoxy-steroid is dissolved in an inert protic solvent and with metallic zinc, for example in powder form, as semolina or as
• Chips in the presence of an aliphatic carboxylic acid or dilute mineral acid, between room temperature and about 100 ° C.
• Suitable inert protic solvents are all those which do not react with the reactants.
• examples include aliphatic alcohols such as methanol, ethanol, n-propanol and isopropyl alcohol, aliphatic and cycloaliphatic ethers such as diisopropyl ether, tetrahydrofuran and dioxane and water.
• formic acid and propionic acid are also suitable as aliphatic carboxylic acid for carrying out the reaction according to the invention.
• dilute mineral acid such as hydrochloric acid or sulfuric acid.
• the acid used is used in excess.
• the excess is 30 to 100 times the amount (molar equivalents).
• the acid is expediently used in a concentration of 0.2-1.0 mol / l.
• the reaction mixture is heated, with a temperature range of 40-70 ° C being preferred.
• the reaction time is about 0.5 to 7 hours, this time depending on the starting material used and in particular on the temperature.
• the course of the reaction according to the invention was surprising, since under the reaction conditions used (acidic, temperature above room temperature) it would have been expected that the 5 ⁇ -hydroxy- ⁇ 6 steroids formed would be converted into corresponding secondary products by allyl rearrangement.
• Morand P. Morand and A. Van Tongerloo, Steroids 21 (1973) 47-611
• 5-hydroxy- ⁇ steroids can be found in the presence of 80% acetic acid at room temperature corresponding allyl rearrangement products, such as 7-hydroxy and 7-acetoxy ⁇ 5 steroids, convert.
• the known aldosterone-antagonistically effective 6ß.7ß can be obtained in the following way, for example; Prepare 15ß.16ß-dimethylene-3-oxo-17 ⁇ -pregn-4-en-21.17-carbolactone:
• reaction solution is diluted with diethyl ether, washed with water, dried and evaporated. 27 g of 3 ⁇ -5-dihydroxy-15ß.16ß-methylene-5ß-androst-6-en-17-one are obtained. Melting point 187-190 ° C (acetone).
• the starting material was produced as follows:
• a solution of 5.0 g of 3 ⁇ -hydroxy-15ß-16ß-methylene-5-androsten-17-one in 50 ml of pyridine was mixed with ice-cooling with 5 ml of benzoyl chloride and then stirred for 17 hours at room temperature. After adding 10 ml of water, stirring was continued for an additional hour, then the reaction solution was diluted with methylene chloride and washed with sodium carbonate solution and water. After drying and evaporation, the residue was triturated with diisopropyl ether and suction filtered. 6.4 g of 3 ⁇ -ben.zoyloxy-15ß.16ß-methylene5-androsten-17-one with a melting point of 250-258 C were obtained.
• Example 2 130 ml of propan-2-ol reacted with 49.5 g of zinc dust as in Example 2 and worked up. After chromatography on silica gel, 8.8 g of 3 ⁇ .l7ß-dibenzoyloxy-15ß.16ß-methylene-5ß-androst-6-en-5-ol are obtained. Melting point 223-225 ° C (acetone diisopropyl ether).
• a solution of 21 g of 3ß-hydroxy-15ß-16ß-methylene-5-androsten-17-one in 210 ml of tetrahydrofuran was treated with 21 g of lithium tri-tert. -Butoxyalanat stirred for 1 hour at room temperature. The mixture was then diluted with diethyl ether, washed with 2N sulfuric acid and water, dried and evaporated. 19 g of 15 ⁇ -16ß methylene-5-androsten-3ß-17ß-diol were obtained, which were used in the next step without further purification.
• 3 ⁇ -Hydroxy-5-androsten-17-one was converted into the 17 ⁇ -acetoxy-3ß-benzoyloxy-5-androsten analogously to Example 2 AC.
• Example 2 D the 17 ⁇ -acetoxy-3ß-benzoyloxy-5-androsten-7-one was prepared from it with tert-butyl chromate.
• Example 1 DF the mixture was reduced, epoxidized and chlorinated, 17ß-acetoxy giving 3 ⁇ -benzoyloxy-7.-chloro-5-6ß-epoxy-5ß-androstane which, after chromatography on silica gel, melted at 173-175.5 ° C.
• Example 5 300 mg of 3 ⁇ -acetoxy-7o-chloro-5.6ß-epoxy-15ß.16ß-methylene 5ß.17 ⁇ -pregnan-21.17-carbolactone in 15 ml of propan-2-ol and 15 ml of acetic acid with 900 mg of zinc dust for 2 hours stirred at 80 C. After filtration, the mixture is diluted with methylene chloride and washed with sodium hydrogen carbonate solution and water, dried over magnesium sulfate and evaporated in vacuo. The residue is purified by preparative thin layer chromatography. 150 mg of 3 ⁇ -acetoxy-5-hydroxy 5ß.17 ⁇ -P-regn-6-en-21.17-carbolactone with a melting point of 209-211 ° C. are obtained.
• a suspension of 20 g of 3 ⁇ -hydroxy-15ß.16ß-methylen5-androsten-17-one in 400 ml of benzene was azeotropically dried by distilling off 40 ml of liquid and mixed with 50 ml of distilled dihydropyran and 250 ml of toluenesulfonic acid at room temperature. After 1 hour at room temperature, 4 ml of pyridine were added, diluted with diethyl ether, washed with sodium hydrogen carbonate solution and water and dried over magnesium sulfate. The one obtained after evaporation

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Steroid Compounds (AREA)

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• 1980
  • 1980-07-11 DE DE3026783A patent/DE3026783C2/de not_active Expired
• 1981
  • 1981-07-02 WO PCT/DE1981/000111 patent/WO1982000294A1/de not_active Ceased
  • 1981-07-02 EP EP81105132A patent/EP0043994B1/de not_active Expired
  • 1981-07-02 AT AT81105132T patent/ATE7791T1/de active
  • 1981-07-02 DE DE8181105132T patent/DE3163971D1/de not_active Expired
  • 1981-07-02 JP JP56502399A patent/JPH0128760B2/ja not_active Expired
  • 1981-07-02 HU HU813202A patent/HU182759B/hu not_active IP Right Cessation
  • 1981-07-02 US US06/359,713 patent/US4472310A/en not_active Expired - Lifetime
  • 1981-08-20 CA CA000384258A patent/CA1156646A/en not_active Expired
• 1982
  • 1982-03-11 DK DK107382A patent/DK107382A/da not_active Application Discontinuation

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