PARTIAL ELECTROCHEMICAL REDUCTION OF 19-NOR-DELTA 1,3,5(10)-STEROIDS
United States Patent 3720694
A-ring aromatic steroids containing an electrolytically reducible group are selectively reduced with the aromatic A-ring intact employing ammonia or an amine as the reaction solvent.
Inventors:
Junghans, Klaus (Berlin, DT)
Ropke, Horst (Berlin, DT)
Ropke, Horst (Berlin, DT)
Application Number:
05/152454
Publication Date:
03/13/1973
Filing Date:
06/11/1971
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Export Citation:
Assignee:
Schering A. G. (Berlin and Bergkamen, DT)
Primary Class:
International Classes:
C25B3/04; C25B3/00; C07C169/32; C07C169/08
Field of Search:
260/397.5
Primary Examiner:
Roberts, Elbert L.
Claims:
What is claimed is
1. A process for the preparation of 19-nor-Δ1,3,5(10) -steroids by selective electrochemical reduction of a 19-nor-Δ1,3,5(10) -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.
2. A process according to claim 1 wherein the electrolytic salt is an onium complex salt having as a central atom an element of Main Group V or VI of the periodic system.
3. A process according to claim 2 wherein the reaction solvent is a compound of the formula NR1 R2 R3 wherein R1, R2 and R3 each are hydrogen, alkyl or aryl.
4. A process according to claim 3 wherein the reaction solvent is liquid ammonia.
5. A process according to claim 1 wherein the electrolytic salt is an alkali-metal or alkaline earth salt.
6. A process according to claim 5 wherein the reaction solvent is liquid ammonia.
7. A process according to claim 2 wherein the reaction solvent comprises as a solubilizer an ether, a chlorinated hydrocarbon, a ketone, an acid functional derivative or water.
8. A process according to claim 2 wherein the electrolysis is conducted at a current density of 10-3 to 5 A/cm2.
9. A process according to claim 2 wherein the electrolysis is conducted at a temperature between -50° C. and the boiling temperature of the solvent.
10. A process according to claim 9 wherein the electrolysis is conducted at a temperature between -50° C. and the boiling temperature of the solvent and the reaction solvent is ammonia, methylamine or ethylamine.
11. A process according to claim 2 wherein the electrolytically reducible functional group is a C=C double bond or a
12. A process according to claim 11 wherein the electrolytic salt is an onium complex salt having as a central atom an element of main Group V or VI of the periodic system.
13. A process according to claim 11 wherein the electrolytic salt is an alkali-metal or alkaline earth salt.
14. A process according to claim 11 wherein the electrolytically reducible functional group is a Δ6, Δ8, Δ9(11), Δ14 or Δ15 double bond.
15. A process according to claim 14 wherein the starting steroid is a 19-nor-Δ1,3,5(10) estratriene having an additional double bond in the C8 -- or C9(11) -position.
16. A process according to claim 15 wherein the electrolytic salt is an onium complex salt having as a central atom an element of Main Group V or VI of the periodic system.
17. A process according to claim 15 wherein the electrolytic salt is an alkali-metal or alkaline earth salt.
1. A process for the preparation of 19-nor-Δ1,3,5(10) -steroids by selective electrochemical reduction of a 19-nor-Δ1,3,5(10) -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.
2. A process according to claim 1 wherein the electrolytic salt is an onium complex salt having as a central atom an element of Main Group V or VI of the periodic system.
3. A process according to claim 2 wherein the reaction solvent is a compound of the formula NR1 R2 R3 wherein R1, R2 and R3 each are hydrogen, alkyl or aryl.
4. A process according to claim 3 wherein the reaction solvent is liquid ammonia.
5. A process according to claim 1 wherein the electrolytic salt is an alkali-metal or alkaline earth salt.
6. A process according to claim 5 wherein the reaction solvent is liquid ammonia.
7. A process according to claim 2 wherein the reaction solvent comprises as a solubilizer an ether, a chlorinated hydrocarbon, a ketone, an acid functional derivative or water.
8. A process according to claim 2 wherein the electrolysis is conducted at a current density of 10-3 to 5 A/cm2.
9. A process according to claim 2 wherein the electrolysis is conducted at a temperature between -50° C. and the boiling temperature of the solvent.
10. A process according to claim 9 wherein the electrolysis is conducted at a temperature between -50° C. and the boiling temperature of the solvent and the reaction solvent is ammonia, methylamine or ethylamine.
11. A process according to claim 2 wherein the electrolytically reducible functional group is a C=C double bond or a
12. A process according to claim 11 wherein the electrolytic salt is an onium complex salt having as a central atom an element of main Group V or VI of the periodic system.
13. A process according to claim 11 wherein the electrolytic salt is an alkali-metal or alkaline earth salt.
14. A process according to claim 11 wherein the electrolytically reducible functional group is a Δ6, Δ8, Δ9(11), Δ14 or Δ15 double bond.
15. A process according to claim 14 wherein the starting steroid is a 19-nor-Δ1,3,5(10) estratriene having an additional double bond in the C8 -- or C9(11) -position.
16. A process according to claim 15 wherein the electrolytic salt is an onium complex salt having as a central atom an element of Main Group V or VI of the periodic system.
17. A process according to claim 15 wherein the electrolytic salt is an alkali-metal or alkaline earth salt.
Description:
BACKGROUND OF THE INVENTION
This invention relates to a novel process for the partial electrochemical reduction of 19-nor-Δ 1 ,3,5(10) -steroids.
It is known that compounds having a plurality of reducible groups in the molecule with differing reduction potential can be electrochemically reduced selectively at a constant cathode potential. See Horner and Singer, Liebigs Ann. Chem. (Liebig's Annals of Chemistry) 723 (1969), 1. However, this process has the disadvantage that it requires a large expenditure in apparatus and time, especially when conducted on an industrial scale.
The electrochemical reduction of simple-structure compounds with conjugated double bonds in the aqueous phase is conventional. See Horner and Roeder, Liebigs Ann. Chem. 723 (1969), 11. However, if this process is applied to sterically complicated molecules, such as unsaturated steroids, e.g., estratetraenes, no reduction takes place.
It is known from German Pat. No. 1,266,300 that unsaturated steroids, such as estratrienes, are reduced in a non-aqueous medium. This process, however, has the disadvantage that the electrochemical reduction is not arrested at the aromatic A-ring. Thus, a partial reduction, which does not attack the aromatic A-ring of the estrenes employed according to the process of this invention, is impossible by the method of German Pat. No. 1,266,300 under the conditions described therein.
Accordingly, there existed in the prior art the problem of partially reducing, with minor expenditure in apparatus and within a short period of time, A-ring unsaturated steroids having other reducible groups in the steroid molecule, with the aromatic A-ring being preserved.
SUMMARY OF THE INVENTION
According to this invention 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.
DETAILLED DISCUSSION
The starting steroids for the process of this invention can be any A-ring aromatic steroid containing an additional group reducible electrolytically. Thus, the starting compounds employed in the process of this invention contain, in addition to the conjugated carbon-to-carbon double bonds of the aromatic A-ring, at least one additional reducible group, e.g., conjugated C=C double bond, e.g., aΔ 6 --,Δ 8 --,Δ 9 (11 --)Δ 14 --,Δ 15 -double bond, and/or a functional group containing an isolated double bond, e.g.,
NO 2 , or C=NR,
wherein R is hydrogen, hydroxy, alkyl or aryl or another reducible group, e.g., the epoxy group. Under the conditions of the process of this invention, an isolated carbon-to-carbon triple bond behaves like a C=C double bond conjugated with respect to the A-ring. The steroid structure can also possess one or more alkyl groups, preferably methyl groups, e.g., in the 1-, 2-, 4-, 6-, 7-, 16- or 18-position, and free, etherified or esterified hydroxy group or groups in the 1-, 3-, 6-, 7-, 11-, 15-, 16- and/or 17-position. A 16- or 17-alkyl group can be of the α- or β-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 ##SPC1##
wherein R is hydrogen, the acyl radical of an organic carboxylic acid, lower-alkyl, preferably methyl, or benzyl; R i and R ii each are hydrogen, fluoro or lower-alkyl, preferably methyl; R iii is hydrogen or α- or β-methyl; R iv is hydrogen or lower-alkyl, preferably methyl or ethyl; X is CH 2 , C=O,
and Y is hydrogen or, when X is carbonyl or methyleneoxy, halo, preferably fluoro, or X and Y collectively represent a 9(11) epoxy group, and Z is C=O,
wherein R v is hydrogen, the acyl radical of an organic carboxylic acid, preferably containing one to 20, most preferably one to eight carbon atoms; and Δ represents a double bond optionally present in one or more of the 6-, 7-, 8-, 8(14)-, 9(11)-, 11-, 14- or 15- positions, and wherein at least one of X or Z is electrolytically reducible or there is present at least one C--C double bond in one of the rings, or both.
Examples of 3- and/or 17-esters of the above formula are those wherein R and/or R v 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.
Other examples are 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,α-ethylbutyric, valeric, isovaleric, α-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., cyclopropylideneacetic, cyclobutylcarboxylic, cyclopentylcarboxylic, cyclopentylacetic, cyclohexyl, cyclohexylacetic and β-cyclohexylpropionic acid; a carbocyclic aryl or alkaryl acid, e.g., containing six to 18 carbon atoms, and one to five, preferable 1 or 2 rings, e.g., benzoic, 2-, 3-, or 4-methylbenzoic, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, and 3,5-dimethylbenzoic, ethylbenzoic, 2,3,6-trimethylbenzoic, and 3-methyl-α-naphthoic acid; an aralkyl acid, e.g., containing seven to 18 carbon atoms, e.g., β-phenylpropionic, a polybasic acid, e.g., containing two to 18 carbon atoms and 1 to 5 hydroxy groups, e.g., glycolic, lactic, citric, tartaric, d-maleic, d-glyceric, and salicylic acid; the corresponding acids containing one, two or more of simple substituents, e.g., halo, alkoxy, acyloxy, etc, in the molecule, e.g., chloroacetic, fluoroacetic, trichloroacetic, trifluoroacetic, 2,3,4-trimethoxybenzoic, phenoxyacetic, α-naphthoxyacetic acid,etc.
Preferred of the compounds of the above formula are those wherein X is CH 2 , R i , R ii , F iii and Y is hydrogen, especially wherein R is lower-alkyl and preferably also wherein R v is hydrogen.
The preparation of the 19-nor-Δ 1 ,3,5(10) -steroids by selective electrochemical reduction is conducted in the presence of an electrolytic salt. Preferred electrolytic salts, which can be used, are onium complex salts or alkalimetal or alkaline earth salts.
Onium salts are onium complexes having as 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.
However, it is possible for the complex to be 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. 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.
Specific examples of alkali-metal and alkaline earth salts are lithium chloride, sodium bromide, potassium jodide, calcium chloride, magnesium chloride, etc.
The reduction is conducted in the presence of a liquid amine or ammonia as reaction solvent. These nitrogen-containing solvents can be represented by the general formula NR 1 R 2 R c8 3 wherein R 1 , R 2 and R 3 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. Especially suitable as solvents are liquid primary and secondary alkyl, aryl and alkyl, aryl amines. However, it is also possible to employ 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 piperidine, or ammonia. Preferred as solvents are the low-molecular primary amines, e.g., lower-alkylamines, especially methylamine and ethylamine, and ammonia. The amines can be employed by themselves or as a mixture.
The addition of another solvent is advantageous, which solvents serve as solubilizers between the amine utilized as solvent and the steroid to be reduced, and simultaneously increase the conductivity. Examples are ethers, 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. In addition to 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 alternating current, direct current, or modulated direct current.
In this connection, the electrolysis conditions, such as potential, amperage, current density, electrode surface area, as well as pressure and temperature can be varied within wide limits. Preferably, the electrolysis is conducted at a current density of 0.001 to 5A/cm 2 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. When employing starting steroids having a Δ 8 double bond, steroids are obtained as products having the natural configuration 8β--H--9α--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 of temperature and pressure.
The compounds prepared according to the present invention are useful as intermediates or for the preparation of valuable pharmaceuticals. Thus, estradiol is obtained, for example, from 3-methoxy-1,3,5(10)- estratrien- 17β-ol by ether splitting. By blocking the 17-keto group of 3-hydroxy-3,5(10), 8-estratetraen-17-one by ketalization during the reduction of this invention, estrone is obtain after ketal splitting, from which ethinyl estradiol is obtained by ethinylation.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
EXAMPLE 1
One gram of 3-methoxy-1,3,5(10),8-estratetraen-17β-ol is electrolyzed between two platinum electrodes in 200 ml. of liquid ammonia containing 5 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-1,3,5(10)-estratrien-17β-ol is obtained, m.p. 85° C.
EXAMPLE 2
One gram of 3-methoxy-1,3,5(10),9(11)-estratetraen-17β-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 1,3,5(10)-estratrien-17β-ol is obtained, m.p. 80° C.
EXAMPLE 3
One gram of 3-methoxy-18-methyl-1,3,5(10),8-estratetraen-17β-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, 0.9 g. of 3-methoxy-18-methyl-1,3,5(10)-estratrien-17β-ol is obtained, m.p. 127° C.
EXAMPLE 4
Two grams of 3-methoxy-1,3,5(10), 8-estratetraen-17β-ol and 10 g. of tetraethylammonium-p-toluenesulfonate are dissolved in 200 ml. of methylamine at -10° C. and electrolyzed for 3 hours between two platinum electrodes, each having a surface area of 1 cm 2 , at a 1 cm. spacing, at 1 A. The methylamine is evaporated at room temperature and the residue is mixed with water. After filtration, 2.0 g. of 3-methoxy-1,3,5(10)-estratrien-17β-ol is obtained, m.p. 94°-96° C.
EXAMPLE 5
One gram of estrone methyl ether dissolved in 100 ml. of tetrahydrofuran is added to a solution of 10 g. of tetraethylammonium-p-toluenesulfonate in 200 ml. of methylamine and electrolyzed for 3 hours between two platinum electrodes (10 cm 2 surface area each, 1 cm. spacing) at 1 A. and -30° C. The solvent mixture is distilled off and the reaction product is precipitated with water and filtered. There is obtained 1.05 g. of 3-methoxy-1,3,5(10)-estratrien-17β-ol, m.p. 93°-95° C.
EXAMPLE 6
One gram of 3-methoxy-1,3,5(10), 8-estratetraen-17-one is electrolyzed for 5 hours in 200 ml. of methylamine together with 10 g. of ethyldimethylcyclohexylammonium-p toluenesulfonate at -10° C. at 1A., using a nickel cathode and a graphite anode (5 cm 2 surface area each, 2 cm. spacing). The methylamine is evaporated and the residue is mixed with water. There is obtained 0.9 g. of 3-methoxy-1,3,5(10)-estratrien-17β-ol, m.p. 94°-96° C. [α] D 20 = +63° (chloroform, c = 1).
EXAMPLE 7
One gram of 3-methoxy-1,3,5(10),8-estratetraen-17β-ol in 200 ml. of ethylamine containing 10 g. of tributylmethylammonium methyl sulfate is electrolyzed with alternating current at 1 A. between two platinum electrodes (respectively 10 cm 2 surface area, 0.5 cm. spacing). After 5 hours, the ethylamine is allowed to evaporate at room temperature. The residue is mixed with water and, after filtration, 0.95 g. of 3-methoxy-1,3,5(10)-estratrien-17β-ol is obtained, m.p. 84°-87° C. [α] D 20 = +64° (chloroform, c = 1).
EXAMPLE 8
One gram of 3-methoxy-1,3,5(10),8-estratetraen-17β-ol in 200 ml. of methylamine containing 10 g. of triethyloxonium tetrafluoroborate is electrolyzed for 3 hours between a stainless steel cathode and a graphite anode (5 cm 2 surface area each, 1 cm. spacing) using rectified alternating current at 1 A. The solvent is evaporated and the reaction product mixed with water. After filtration, 0.9 g. of 3-methoxy-1,3,5(10)-estratrien-17β-ol is obtained, m.p. 84°-85° C.
EXAMPLE 9
Two grams of 3-methoxy-1,3,5(10),8-estratetraen-17β-ol is dissolved in 30 ml. of tetrahydrofuran and added dropwise, under agitation, to a mixture of 10 g. of tributylmethylphosphonium-p-toluenesulfonate, 200 ml. of methylamine, and 2 ml. of water. The reaction mixture is electrolyzed for 10 hours between two platinum electrodes (10 cm 2 surface area each, 0.5 cm. spacing). The methylamine is evaporated and the residue is mixed with water. After filtration, there is obtained 2.0 g. of 3-methoxy-1,3,5(10)-estratrien-17β-ol, m.p. 90°-95° C.
EXAMPLE 10
Two grams of 3-methoxy-1,3,5(10),8-estratetraen-17β-ol in 30 ml. of dioxane is added to a solution of 15 g. of trimethylcetylammonium-p-toluenesulfonate in 200 ml. of ethylenediamine and electrolyzed between two platinum electrodes (10 cm 2 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-1,3,5(10)estratrien-17β-ol, m.p. 94°-96° C.
EXAMPLE 11
One gram of 3-methoxy-1,3,5(10), 8-estratetraen-17-one and 10 g. of tributylethylammonium tetrafluoroborate in 200 ml. of methylamine are electrolyzed between a cathode of stainless steel and a platinum anode (5 cm 2 surface area each). After the reduction is terminated, the solvent is allowed to evaporate. The residue is mixed with water. After filtration, 1.0 g. of 3-methoxy-1,3,5(10)-estratrien-17β-ol is obtained, m.p. 94°-95° C.
EXAMPLE 12
Two grams of 3-methoxy-1,3,5(10 ),9(11)-estratetraen-17β-ol and 10 g. of tetrabutylammonium iodide in 150 ml. of methylamine are electrolyzed at 1 A. between two platinum foils (1 cm 2 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-1,3,5(10)-estratrien-17β-ol, m.p. 98° C.
EXAMPLE 13
A solution of one gram of 3-methoxy-1,3,5(10),9(11)-estratetraen-17β-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 1 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-1,3,5(10)-estratrien-17β-ol, m.p. 92°-94° C.
EXAMPLE 14
Two grams of 3-methoxy-1,3,5(10),8-estratetraen-17β-ol and 20 g. of tri-n-butylmethylammonium methyl sulfate in 200 ml. of methylamine are electrolyzed at 1 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-1,3,5(10)-estratrien-17β-ol, m.p. 92°-93° C.
EXAMPLE 15
One gram of 3-methoxy-1,3,5(10),8-estratetraene-17α-ethinyl-17β-ol in 50 ml. of tetrahydrofuran is electrolyzed between two platinum electrodes (0.5 cm 2 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-methoxy-1,3,5(10)-estratriene- 17α-vinyl-17β-ol, m.p. 108°-110° C.
EXAMPLE 16
One gram of 3-methoxy-17α-ethyl-17β-hydroxy-1,3,5(10),8-estratetraene is electrolyzed between two platinum electrodes (100 cm 2 surface area each, 0.5 cm. spacing) at 1 A. in 200 ml. of methylamine containing 10 g. of tetrabutylammonium sulfate. After the reaction is terminated, the solvent is evaporated and the residue mixed with water and filtered, thus obtaining 1.0 g. of 3-methoxy-17α-ethyl-17β-hydroxy-1,3,5(10)-estratriene, m.p. 93°-100° C.
The preceding examples can be repeated with similar success by substituting the generically and specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.
This invention relates to a novel process for the partial electrochemical reduction of 19-nor-Δ 1 ,3,5(10) -steroids.
It is known that compounds having a plurality of reducible groups in the molecule with differing reduction potential can be electrochemically reduced selectively at a constant cathode potential. See Horner and Singer, Liebigs Ann. Chem. (Liebig's Annals of Chemistry) 723 (1969), 1. However, this process has the disadvantage that it requires a large expenditure in apparatus and time, especially when conducted on an industrial scale.
The electrochemical reduction of simple-structure compounds with conjugated double bonds in the aqueous phase is conventional. See Horner and Roeder, Liebigs Ann. Chem. 723 (1969), 11. However, if this process is applied to sterically complicated molecules, such as unsaturated steroids, e.g., estratetraenes, no reduction takes place.
It is known from German Pat. No. 1,266,300 that unsaturated steroids, such as estratrienes, are reduced in a non-aqueous medium. This process, however, has the disadvantage that the electrochemical reduction is not arrested at the aromatic A-ring. Thus, a partial reduction, which does not attack the aromatic A-ring of the estrenes employed according to the process of this invention, is impossible by the method of German Pat. No. 1,266,300 under the conditions described therein.
Accordingly, there existed in the prior art the problem of partially reducing, with minor expenditure in apparatus and within a short period of time, A-ring unsaturated steroids having other reducible groups in the steroid molecule, with the aromatic A-ring being preserved.
SUMMARY OF THE INVENTION
According to this invention 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.
DETAILLED DISCUSSION
The starting steroids for the process of this invention can be any A-ring aromatic steroid containing an additional group reducible electrolytically. Thus, the starting compounds employed in the process of this invention contain, in addition to the conjugated carbon-to-carbon double bonds of the aromatic A-ring, at least one additional reducible group, e.g., conjugated C=C double bond, e.g., aΔ 6 --,Δ 8 --,Δ 9 (11 --)Δ 14 --,Δ 15 -double bond, and/or a functional group containing an isolated double bond, e.g.,
NO 2 , or C=NR,
wherein R is hydrogen, hydroxy, alkyl or aryl or another reducible group, e.g., the epoxy group. Under the conditions of the process of this invention, an isolated carbon-to-carbon triple bond behaves like a C=C double bond conjugated with respect to the A-ring. The steroid structure can also possess one or more alkyl groups, preferably methyl groups, e.g., in the 1-, 2-, 4-, 6-, 7-, 16- or 18-position, and free, etherified or esterified hydroxy group or groups in the 1-, 3-, 6-, 7-, 11-, 15-, 16- and/or 17-position. A 16- or 17-alkyl group can be of the α- or β-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 ##SPC1##
wherein R is hydrogen, the acyl radical of an organic carboxylic acid, lower-alkyl, preferably methyl, or benzyl; R i and R ii each are hydrogen, fluoro or lower-alkyl, preferably methyl; R iii is hydrogen or α- or β-methyl; R iv is hydrogen or lower-alkyl, preferably methyl or ethyl; X is CH 2 , C=O,
and Y is hydrogen or, when X is carbonyl or methyleneoxy, halo, preferably fluoro, or X and Y collectively represent a 9(11) epoxy group, and Z is C=O,
wherein R v is hydrogen, the acyl radical of an organic carboxylic acid, preferably containing one to 20, most preferably one to eight carbon atoms; and Δ represents a double bond optionally present in one or more of the 6-, 7-, 8-, 8(14)-, 9(11)-, 11-, 14- or 15- positions, and wherein at least one of X or Z is electrolytically reducible or there is present at least one C--C double bond in one of the rings, or both.
Examples of 3- and/or 17-esters of the above formula are those wherein R and/or R v 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.
Other examples are 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,α-ethylbutyric, valeric, isovaleric, α-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., cyclopropylideneacetic, cyclobutylcarboxylic, cyclopentylcarboxylic, cyclopentylacetic, cyclohexyl, cyclohexylacetic and β-cyclohexylpropionic acid; a carbocyclic aryl or alkaryl acid, e.g., containing six to 18 carbon atoms, and one to five, preferable 1 or 2 rings, e.g., benzoic, 2-, 3-, or 4-methylbenzoic, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, and 3,5-dimethylbenzoic, ethylbenzoic, 2,3,6-trimethylbenzoic, and 3-methyl-α-naphthoic acid; an aralkyl acid, e.g., containing seven to 18 carbon atoms, e.g., β-phenylpropionic, a polybasic acid, e.g., containing two to 18 carbon atoms and 1 to 5 hydroxy groups, e.g., glycolic, lactic, citric, tartaric, d-maleic, d-glyceric, and salicylic acid; the corresponding acids containing one, two or more of simple substituents, e.g., halo, alkoxy, acyloxy, etc, in the molecule, e.g., chloroacetic, fluoroacetic, trichloroacetic, trifluoroacetic, 2,3,4-trimethoxybenzoic, phenoxyacetic, α-naphthoxyacetic acid,etc.
Preferred of the compounds of the above formula are those wherein X is CH 2 , R i , R ii , F iii and Y is hydrogen, especially wherein R is lower-alkyl and preferably also wherein R v is hydrogen.
The preparation of the 19-nor-Δ 1 ,3,5(10) -steroids by selective electrochemical reduction is conducted in the presence of an electrolytic salt. Preferred electrolytic salts, which can be used, are onium complex salts or alkalimetal or alkaline earth salts.
Onium salts are onium complexes having as 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.
However, it is possible for the complex to be 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. 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.
Specific examples of alkali-metal and alkaline earth salts are lithium chloride, sodium bromide, potassium jodide, calcium chloride, magnesium chloride, etc.
The reduction is conducted in the presence of a liquid amine or ammonia as reaction solvent. These nitrogen-containing solvents can be represented by the general formula NR 1 R 2 R c8 3 wherein R 1 , R 2 and R 3 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. Especially suitable as solvents are liquid primary and secondary alkyl, aryl and alkyl, aryl amines. However, it is also possible to employ 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 piperidine, or ammonia. Preferred as solvents are the low-molecular primary amines, e.g., lower-alkylamines, especially methylamine and ethylamine, and ammonia. The amines can be employed by themselves or as a mixture.
The addition of another solvent is advantageous, which solvents serve as solubilizers between the amine utilized as solvent and the steroid to be reduced, and simultaneously increase the conductivity. Examples are ethers, 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. In addition to 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 alternating current, direct current, or modulated direct current.
In this connection, the electrolysis conditions, such as potential, amperage, current density, electrode surface area, as well as pressure and temperature can be varied within wide limits. Preferably, the electrolysis is conducted at a current density of 0.001 to 5A/cm 2 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. When employing starting steroids having a Δ 8 double bond, steroids are obtained as products having the natural configuration 8β--H--9α--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 of temperature and pressure.
The compounds prepared according to the present invention are useful as intermediates or for the preparation of valuable pharmaceuticals. Thus, estradiol is obtained, for example, from 3-methoxy-1,3,5(10)- estratrien- 17β-ol by ether splitting. By blocking the 17-keto group of 3-hydroxy-3,5(10), 8-estratetraen-17-one by ketalization during the reduction of this invention, estrone is obtain after ketal splitting, from which ethinyl estradiol is obtained by ethinylation.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
EXAMPLE 1
One gram of 3-methoxy-1,3,5(10),8-estratetraen-17β-ol is electrolyzed between two platinum electrodes in 200 ml. of liquid ammonia containing 5 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-1,3,5(10)-estratrien-17β-ol is obtained, m.p. 85° C.
EXAMPLE 2
One gram of 3-methoxy-1,3,5(10),9(11)-estratetraen-17β-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 1,3,5(10)-estratrien-17β-ol is obtained, m.p. 80° C.
EXAMPLE 3
One gram of 3-methoxy-18-methyl-1,3,5(10),8-estratetraen-17β-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, 0.9 g. of 3-methoxy-18-methyl-1,3,5(10)-estratrien-17β-ol is obtained, m.p. 127° C.
EXAMPLE 4
Two grams of 3-methoxy-1,3,5(10), 8-estratetraen-17β-ol and 10 g. of tetraethylammonium-p-toluenesulfonate are dissolved in 200 ml. of methylamine at -10° C. and electrolyzed for 3 hours between two platinum electrodes, each having a surface area of 1 cm 2 , at a 1 cm. spacing, at 1 A. The methylamine is evaporated at room temperature and the residue is mixed with water. After filtration, 2.0 g. of 3-methoxy-1,3,5(10)-estratrien-17β-ol is obtained, m.p. 94°-96° C.
EXAMPLE 5
One gram of estrone methyl ether dissolved in 100 ml. of tetrahydrofuran is added to a solution of 10 g. of tetraethylammonium-p-toluenesulfonate in 200 ml. of methylamine and electrolyzed for 3 hours between two platinum electrodes (10 cm 2 surface area each, 1 cm. spacing) at 1 A. and -30° C. The solvent mixture is distilled off and the reaction product is precipitated with water and filtered. There is obtained 1.05 g. of 3-methoxy-1,3,5(10)-estratrien-17β-ol, m.p. 93°-95° C.
EXAMPLE 6
One gram of 3-methoxy-1,3,5(10), 8-estratetraen-17-one is electrolyzed for 5 hours in 200 ml. of methylamine together with 10 g. of ethyldimethylcyclohexylammonium-p toluenesulfonate at -10° C. at 1A., using a nickel cathode and a graphite anode (5 cm 2 surface area each, 2 cm. spacing). The methylamine is evaporated and the residue is mixed with water. There is obtained 0.9 g. of 3-methoxy-1,3,5(10)-estratrien-17β-ol, m.p. 94°-96° C. [α] D 20 = +63° (chloroform, c = 1).
EXAMPLE 7
One gram of 3-methoxy-1,3,5(10),8-estratetraen-17β-ol in 200 ml. of ethylamine containing 10 g. of tributylmethylammonium methyl sulfate is electrolyzed with alternating current at 1 A. between two platinum electrodes (respectively 10 cm 2 surface area, 0.5 cm. spacing). After 5 hours, the ethylamine is allowed to evaporate at room temperature. The residue is mixed with water and, after filtration, 0.95 g. of 3-methoxy-1,3,5(10)-estratrien-17β-ol is obtained, m.p. 84°-87° C. [α] D 20 = +64° (chloroform, c = 1).
EXAMPLE 8
One gram of 3-methoxy-1,3,5(10),8-estratetraen-17β-ol in 200 ml. of methylamine containing 10 g. of triethyloxonium tetrafluoroborate is electrolyzed for 3 hours between a stainless steel cathode and a graphite anode (5 cm 2 surface area each, 1 cm. spacing) using rectified alternating current at 1 A. The solvent is evaporated and the reaction product mixed with water. After filtration, 0.9 g. of 3-methoxy-1,3,5(10)-estratrien-17β-ol is obtained, m.p. 84°-85° C.
EXAMPLE 9
Two grams of 3-methoxy-1,3,5(10),8-estratetraen-17β-ol is dissolved in 30 ml. of tetrahydrofuran and added dropwise, under agitation, to a mixture of 10 g. of tributylmethylphosphonium-p-toluenesulfonate, 200 ml. of methylamine, and 2 ml. of water. The reaction mixture is electrolyzed for 10 hours between two platinum electrodes (10 cm 2 surface area each, 0.5 cm. spacing). The methylamine is evaporated and the residue is mixed with water. After filtration, there is obtained 2.0 g. of 3-methoxy-1,3,5(10)-estratrien-17β-ol, m.p. 90°-95° C.
EXAMPLE 10
Two grams of 3-methoxy-1,3,5(10),8-estratetraen-17β-ol in 30 ml. of dioxane is added to a solution of 15 g. of trimethylcetylammonium-p-toluenesulfonate in 200 ml. of ethylenediamine and electrolyzed between two platinum electrodes (10 cm 2 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-1,3,5(10)estratrien-17β-ol, m.p. 94°-96° C.
EXAMPLE 11
One gram of 3-methoxy-1,3,5(10), 8-estratetraen-17-one and 10 g. of tributylethylammonium tetrafluoroborate in 200 ml. of methylamine are electrolyzed between a cathode of stainless steel and a platinum anode (5 cm 2 surface area each). After the reduction is terminated, the solvent is allowed to evaporate. The residue is mixed with water. After filtration, 1.0 g. of 3-methoxy-1,3,5(10)-estratrien-17β-ol is obtained, m.p. 94°-95° C.
EXAMPLE 12
Two grams of 3-methoxy-1,3,5(10 ),9(11)-estratetraen-17β-ol and 10 g. of tetrabutylammonium iodide in 150 ml. of methylamine are electrolyzed at 1 A. between two platinum foils (1 cm 2 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-1,3,5(10)-estratrien-17β-ol, m.p. 98° C.
EXAMPLE 13
A solution of one gram of 3-methoxy-1,3,5(10),9(11)-estratetraen-17β-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 1 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-1,3,5(10)-estratrien-17β-ol, m.p. 92°-94° C.
EXAMPLE 14
Two grams of 3-methoxy-1,3,5(10),8-estratetraen-17β-ol and 20 g. of tri-n-butylmethylammonium methyl sulfate in 200 ml. of methylamine are electrolyzed at 1 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-1,3,5(10)-estratrien-17β-ol, m.p. 92°-93° C.
EXAMPLE 15
One gram of 3-methoxy-1,3,5(10),8-estratetraene-17α-ethinyl-17β-ol in 50 ml. of tetrahydrofuran is electrolyzed between two platinum electrodes (0.5 cm 2 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-methoxy-1,3,5(10)-estratriene- 17α-vinyl-17β-ol, m.p. 108°-110° C.
EXAMPLE 16
One gram of 3-methoxy-17α-ethyl-17β-hydroxy-1,3,5(10),8-estratetraene is electrolyzed between two platinum electrodes (100 cm 2 surface area each, 0.5 cm. spacing) at 1 A. in 200 ml. of methylamine containing 10 g. of tetrabutylammonium sulfate. After the reaction is terminated, the solvent is evaporated and the residue mixed with water and filtered, thus obtaining 1.0 g. of 3-methoxy-17α-ethyl-17β-hydroxy-1,3,5(10)-estratriene, m.p. 93°-100° C.
The preceding examples can be repeated with similar success by substituting the generically and specifically described reactants and/or operating conditions of this invention for those used in the preceding examples.
From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.