Classifications

• • C—CHEMISTRY; METALLURGY
  • C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
  • C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
  • C25B3/00—Electrolytic production of organic compounds
  • C25B3/20—Processes
  • C25B3/25—Reduction
• • C—CHEMISTRY; METALLURGY
  • C25—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES; APPARATUS THEREFOR
  • C25B—ELECTROLYTIC OR ELECTROPHORETIC PROCESSES FOR THE PRODUCTION OF COMPOUNDS OR NON-METALS; APPARATUS THEREFOR
  • C25B3/00—Electrolytic production of organic compounds
  • C25B3/01—Products
  • C25B3/07—Oxygen containing compounds

Definitions

• This invention relates toa novel process for the partial electrochemical reduction of l9-nor-A"' "-steroids.
• A-ring aromatic steroids are produced by the selective electrolytic reduction of A-ring aromatic steroids having at least one additional reducible group in the molecule, by conducting the reduction at constant current in the presence of an electrolytic salt and ammonia or an amine as the reaction solvent alone, or optionally as a mixture with a solubilizer for the steroid.
• the starting steroids for the process of this invention can be any A-ring aromaticsteroid containing an additional group reducible electrolytically.
• o groups preferably methyl groups, e.g., in the l-, 2-, 4-,
• a 16- or l7-alkyl group can be of the aor fl-configuration.
• Alkyl as used herein means one to eight carbon atoms, preferably one to four.
• Preferred as starting steroids are A-ring aromatic steroids of the formula T. X x
• R" is hydrogen, the acyl radical of an organic carboxylic acid, preferably containing one to 20, most preferably one to eight carbon atoms; and A represents a double bond optionally present in one or more of the 6-, 7-, 8-, 8( l4)-, 9(l l ll-, l4- or l5- positions, and
• Examples of 3- and/or l7-esters of the above formula are those wherein R and/or R is the acyl radical of an organic carboxylic acid of up to 15 carbon atoms, especially lower (one to six) carbon atoms and intermediate (seven to 12) aliphatic carboxylic, preferably alkanoic acids.
• the acyl-radical can be unsaturated, branched, polybasic, or substituted in the usual manner, for example by hydroxy or halogen atoms.
• Also suitable are cycloaliphatic, aromatic and mixed aromatic-aliphatic (alkaryl and aralkyl), which can likewise be substituted in the usual manner.
• Examples of preferred acids are acetic acid, propionic acid, caproic acid, enanthic acid,
• undecylic acid oleic acid, trimethylacetic acid, dichloroacetic acid, cyclopentylpropionic acid, phenylpropionic acid, phenylacetic acid, phenoxyacetic acid, succinic acid, benzoic acid, and others.
• acids containing 1-18, preferable 2-12 carbon atoms wherein the acyl group is the acyl radical of, for example, an aliphatic acid containing one to 18, preferably one to six carbon atoms, e.g., formic, butyric, isobutyriC,a-ethylbutyric, valeric, isovaleric, a-ethylvaleric, 2-methylbutyric, 3-ethylbutyric, hexanoic, diethylacetic, triethalacetic, enanthic, octanoic undecylic and palmitic, a cyclic acid, preferably a cycloaliphatic acid, containing, e.g., five to 18 carbon atoms, e.g., cyclopropylidcneacetic, cyclohutylcarboxylic, cyclopentylcarboxylic, cyclopentylacetic, cyclohexyl
• Preferred of the compounds of the above formula are those wherein X is CH R', R", F' and Y is hydrogen, especially wherein R is lower-alkyl and preferably also wherein R" is hydrogen.
• electrolytic salts which can be used, are onium complex salts or alkalimetal or alkaline earth salts.
• Onium salts are onium complexes havingas the central atom an element of Main Group V or VI of the periodic system, e.g., ammonium, phosphonium, oxonium, and sulfonium salts, wherein straight-chain or branched alkyl groups of up to 20, preferably one to eight and more preferably one to four, carbon atoms are preferably employed as the ligands.
• the complex is formed by hydrogen or by binary ligands (chelate complexes) wherein the carbon atoms form an optionally substituted alicyclic ring of 4-10 members which can also be, in part, substituted by hetero atoms, e.g., nitrogen, sulfur, and oxygen.
• binary ligands chelate complexes
• hetero atoms e.g., nitrogen, sulfur, and oxygen.
• the anion necessary for charge equalization has no influence on the process of this invention. Examples are simple anions, e.g., halogenides, or complex anions, e.g., tetrafluoroborate, sulfate, perchlorate, or aryl and alkyl sulfonates.
• alkali-metal and alkaline earth salts are lithium chloride, sodium bromide, potassium jodide, calcium chloride, magnesium chloride, etc.
• a liquid amine or ammonia as reaction solvent.
• nitrogen-containing solvents can be represented by the general formula NR R R 3 wherein R',, R and R each are hydrogen, alkyl or aryl.
• Alkyl can contain one to 15, preferably one to six, carbon atoms, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, octyl, etc.
• Aryl can contain from six to 15 preferably six to eight carbon atoms, e.g., phenyl, p-tolyl, xylyl, 3-ethylphenyl, diphenyl, p-benzylphenyl, p-(2-phenylisopropyl-)phenyl, benzyl, benzhydryl, phenethyl, etc.
• solvents are liquid primary and secondary alkyl, aryl and alkyl, aryl amines.
• tertiary amines e.g., tert.-butylamine
• amines with two or more amino groups e.g., ethylenediamine, cycloaliphatic amines, e.g., cyclohexylamine, heterocyclic amines, e.g., pyrrolidine and pipcridine, or ammonia.
• Preferred as solvents are the low-molecular primary amines, e.g., lower-alkylamincs, especially methylamine and ethylamine, and ammonia.
• the amines can be employed by themselves or as a mixture.
• solvents serve as solubilizers between the amine utilized as solvent and the steroid to be reduced, and simultaneously increase the conductivity.
• solvents e.g., diethyl ether, tetrahydrofuran, or dioxane
• acid derivatives e.g., ethyl acetate, acetonitrile, dimethylformamide, and also dimethyl sulfoxide and chlorinated hydrocarbons, e.g., methylene chloride, chloroform and trichloroethylene.
• inert organic solvents it is also possible to employ a limited amount of water for this purpose.
• the concentration of electrolytic salt and steroid to be reduced does not significantly affect the reduction process and can be varied over a wide range.
• the reduction is not impaired if a portion thereof is present as a solid phase (saturated solution).
• the electrolysis is conducted in a one-piece cell. It is possible to employ alternating current, rectified alterv nating current, direct current, or modulated direct current.
• the electrolysis conditions such as potential, amperage, current density, electrode surface area, as well as pressure and temperature can be varied within wide limits.
• the electrolysis is conducted at a current density of 0.001 to SA/cm and at a temperature of between 50 C. and the boiling point of the solvent.
• the electrode material is likewise noncritical, i.e., it must merely conduct current and be stable under the electrolysis conditions. Examples in this connection are graphite or platinum.
• the electrolysis process can be conducted continuously or discontinuously.
• the process of this invention has the advantage that the reduction takes place stereospecifically.
• steroids are obtained as products having the natural configuration 8B--H--9a--H.
• the process of this invention has the advantage that it requires relatively few pieces of apparatus. Also, the electrolysis can be conducted within a short period of time. Furthermore, the reduction is substantially independent oftemperature and pressure.
• estradiol is obtained, for example, from B-methoxy- 1,3,5(10)- estratrien-l7/3-ol by ether splitting.
• estrone is obtained after ketal splitting,
• EXAMPLE 1 One gram of 3-methoxy-1,3,5( l),8-estratetraen- 1713-01 is electrolyzed between two platinum electrodes in 200 ml. of liquid ammonia containing g. of LiCl. After the reduction is terminated, the solvent is allowed to evaporate. The residue is mixed with water. After filtration, 0.9 g. of 3-methoxy-l,3,5(l0)-estratrien-l7[3- 01 is obtained, m.p. 85C.
• EXAMPLE 2 One gram of 3-methoxy-l ,3,5( l0),9( l 1 )-estratetraen-l7B-ol .is electrolyzed between platinum electrodes in 200 ml. of liquid ammonia containing 5 g. of sodium perchlorate and 3 ml. of dioxane. After the reduction is terminated, the solvent is allowed to evaporate, the residue is decomposed with dilute acetic acid, and after filtration, 0.8 g. of l,3,5( l0)-estratrienl7B-ol is obtained, m.p. 80 C.
• EXAMPLE 3 One gram of 3-methoxy-l8-methyl-l ,3,5( l0),8-estratetraen-l7B-ol is electrolyzed between platinum electrodes in 200 ml. of liquid ammonia containing 5 g. of magnesium tetrafluoroborate. After the reduction is terminated, the solvent is allowed to evaporate. The residue is mixed with water. After filtration, 0.9g. of 3- methoxyl 8-methyl-l ,3,5('l 0)-estratrien-l 75-0] is obtained, m.p. l27C.
• EXAMPLE 4 Two grams of 3-methoxy-l ,3,5( l0),8-estratetraen- 175-0] and 10 g. of tetraethylammonium-p-toluenesulfonate are dissolved in 200 ml. of methylamine at l0 C. and electrolyzed for 3 hours between ,two platinum electrodes, each having a surface area of 1 cm, at a 1 cm. spacing, at l A. The methylamine is evaporated at room temperature and the residue is mixed with water. After filtration, 2.0 g. of 3-methoxy-l ,3,5( l0)-estratrien-l 73-0] is obtained, m.p. 9496 C.
• EXAMPLE 7 One gram of 3-methoxy-l,3,5(10),8-estratetraenl7B-ol in 200 ml. of ethylamine containing 10 g. of tributylmethylammonium methyl sulfate is electrolyzed with alternating current at l A. between two platinum electrodes (respectively 10 cm surface area, 0.5 cm. spacing). After'S hours, the ethylamine is allowed to evaporate at room temperature. The residue is mixed with water and, after filtration, 0.95 g. of S-methoxyl,3,5(l0)-estratrien-l7B-ol is obtained, m.p. 8487 C.
• EXAMPLE 9 Two grams of 3-methoxy-l,3,5(l0),8-estratetraenl7B-ol in 30 ml. of dioxane is added to a solution of 15 g. of trimethylcetylammonium-p-toluenesulfonate in 200ml. of ethylenediamine and electrolyzed between two platinum electrodes (10 cm surface area each, 0.5 cm. spacing). After the reduction is terminated, the solution is evaporated to dryness under vacuum. The residue is mixed with water and filtered, thus obtaining 1.9 g. of 3-methoxy-l,3,5(l0)estratrien-l7B-ol, m.p. 94-96 C.
• EXAMPLE 12 Two grams of 3-methoxy-l,3,5(l0 ),9(1l)-estratetraen-l7B-ol and g. of tetrabutylammonium iodide in ISO ml. of methylamine are electrolyzed at l A. between two platinum foils (l cm surface area each, 1 cm. spacing). After the reduction is terminated, the methylamine is allowed to evaporate and the residue is mixed with water. After filtration there is thus obtained 1.9 g. of 3-methoxy-l ,3,5( l0)-estratrienl7B-ol, m.p. 98 C.
• EXAMPLE 13 A solution of one gram of 3-methoxy-l,3,5( l0 ),9(ll)-estratetraen-l7B-ol in 50 ml. of tetrahydrofuran is added to a mixture of 200 ml. of methylamine and 10 g. of tributylsulfonium-p-toluenesulfonate, and electrolyzed at l A. between two platinum electrodes. After the reaction is terminated, the reaction mixture is evaporated to dryness under vacuum and the residue is mixed with water and filtered. There is thus obtained 1.0 g. of 3-methoxy-l,3,5(l0)-estratrien-l7B-ol, m.p. 9294 C.
• EXAMPLE 14 Two grams of 3-methoxy-l,3,5(10),8-estratetraen- 173-01 and 20 g. of tri-n-butylmethylammonium methyl sulfate in 200 ml. of methylamine are electrolyzed at l A. After the reduction is terminated, the mixture is concentrated by evaporation. The residue is mixed with water and worked up, thus obtaining 1.9 g. of 3- methoxy-l ,3,5( lO)-estratrien-l7B-ol, m.p. 9293 C.
• EXAMPLE 15 One gram of 3-methoxy-l,3,5(l0),8-estratetraenel7a-ethinyl-l7B-ol in 50 ml. of tetrahydrofuran is electrolyzed between two platinum electrodes (0.5 cm surface area each at 2 A) in 200 ml. of ammonia containing 10 g. of tetrabutylammonium-p-toluenesulfonate. After the reduction is terminated, the solvent is evaporated and the reaction mixture worked up, thus obtaining 1.0 g. of 3-meth0xy-l ,3,5(10)-estratrienel7a-vinyl-l7B-ol, m.p. 108-l 10C.
• a process for the preparation of l9-nor-A-"""”" steroids by selective electrochemical reduction of a 19- nor-A-' -steroid containing at least one electrolytically reducible functional group having an isolated double or triple bond or containing at least one conjugated carbon-to-carbon double bond in the molecule which comprises conducting the reduction at a constant current in ammonia or an amine solvent and in the presence of an electrolytic salt.
• electrolytic salt is an onium complex salt having as a central atom an element of Main Group V or V1 of the periodic system.
• reaction solvent is a compound of the formula NR R R wherein R,, R and R each are hydrogen, alkyl or aryl.
• reaction solvent is liquid ammonia
• electrolytic salt is an alkali-metal or alkaline earth salt.
• reaction solvent is liquid ammonia
• reaction solvent comprises as a solubilizer an ether, a chlorinated hydrocarbon, a ketone, an acid functional derivative or water.
• electrolytic salt is an onium complex salt having as a central atom an element of main Group V or V1 of the periodic system.
• a process according to claim 11 wherein the electrolytic salt is an alkali-metal or alkaline earth salt.
• a process a rding to Claim wherein the 16 A process according to claim 15 wherein the electrolytic salt is an alkali-metal or alkaline earth salt. electrolytic salt is an onium complex salt having as a 5

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Electrochemistry (AREA)
• Materials Engineering (AREA)
• Metallurgy (AREA)
• Steroid Compounds (AREA)
• Electrolytic Production Of Non-Metals, Compounds, Apparatuses Therefor (AREA)

Applications Claiming Priority (2)

Publications (1)

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Country Status (9)

Cited By (4)

• 1971
  • 1971-05-24 CH CH755671A patent/CH606087A5/xx not_active IP Right Cessation
  • 1971-06-01 CS CS4007A patent/CS171234B2/cs unknown
  • 1971-06-03 DK DK270671AA patent/DK124880B/da unknown
  • 1971-06-07 GB GB1917371*[A patent/GB1356433A/en not_active Expired
  • 1971-06-10 NL NL7107997A patent/NL7107997A/xx not_active Application Discontinuation
  • 1971-06-11 US US00152454A patent/US3720694A/en not_active Expired - Lifetime
  • 1971-06-11 FR FR7121262A patent/FR2096231A5/fr not_active Expired
  • 1971-06-11 BE BE768423A patent/BE768423A/xx unknown
  • 1971-06-11 JP JP4160971A patent/JPS531268B1/ja active Pending
• 1977
  • 1977-03-02 CH CH260777A patent/CH606092A5/xx not_active IP Right Cessation

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