CA1170651A - 8.alpha.-OESTRA-1,3,5(10)-TRIENE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS - Google Patents
8.alpha.-OESTRA-1,3,5(10)-TRIENE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONSInfo
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Abstract
NEW 8.alpha.-OESTRA-1,3,5(10)-TRIENE DERIVATIVES, PROCESSES
FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS.
ABSTRACT
The invention relates to new 8.alpha.-oestra-1,3,5(10)-triene derivatives having the formula:
in which R1 = H or a free, esterified or etherified hydroxy group;
R2 = H or a free, esterified or etherified hydroxy group, with the proviso that at least one of the substituents R1 and R2 is different from H;
R3 = alkyl (1-4 C) and R4 = O or (.alpha.X) (.beta.Y), in which X = H or aliphatic hydrocarbyl (1-4 C) and Y = a free, esterified or etherified hydroxy group and the enantiomers and racemic mixtures thereof, and also extends to processes for their preparation and to pharmaceutical compositions containing said new compounds.
FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS.
ABSTRACT
The invention relates to new 8.alpha.-oestra-1,3,5(10)-triene derivatives having the formula:
in which R1 = H or a free, esterified or etherified hydroxy group;
R2 = H or a free, esterified or etherified hydroxy group, with the proviso that at least one of the substituents R1 and R2 is different from H;
R3 = alkyl (1-4 C) and R4 = O or (.alpha.X) (.beta.Y), in which X = H or aliphatic hydrocarbyl (1-4 C) and Y = a free, esterified or etherified hydroxy group and the enantiomers and racemic mixtures thereof, and also extends to processes for their preparation and to pharmaceutical compositions containing said new compounds.
Description
J ~j '; .t NEW 8a-OESTRA-1,3,5(10)-TRIENE DERIVATIVES, PROCESSES
FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS.
The invention relates to new 8a-oestra-1,3,5(10)-triene derivatives, processes for preparing these new 8a-steroids and to pharmaceutical compositions containing one or more of these new 8~-steroids as active constituent. The invention relates particularly to new 8a-oestra-1,3,5(10)-triene compounds having an 11-alkyl(1-4 C) substituent.
8a-steroids (or 8-iso-steroids) of the oestrane series are already known, see for example J~A.C.S. 80, 661 (1958); J.Med.Chem. 9, 338 (1966), Steroids 28, 325 (1976), U.S. patent 3 465 011.
A group of new 8a-oestra-1,3,5(10)-triene derivatives with interesting biological pro~perties has now been discovered, which is substituted at the lla-position by an alkyl group having 1-4 carbon atoms. The new 8a-compounds have the following ~ formula (1):
:
~ 20 1 ~ 1 3~
R3."
R
wherein Rl = H or a free, esterified or etherified hydroxy group R2 = H or a free, esterified or etherified hydroxy group, with the proviso that at least one of the substituents Rl and R2 is dissimilar to H
R3 = alkyl (1-4 C); and R4 = 0 or (X) (~Y), in which X = H or aliphatic hydrocarbyl (1=4 C) and Y = a free, esterified or etherified hydroxy group.
This invention also provides for a process for the preparation of novel 8a-oestra-1,3,5(10)-triene derivatives substituted at the lla-position by an alkyl group with 1-4 carbon atoms and have the formula (1):
r ~
wherein Rl stands for H or a free, esterified or etherified hydroxy group; R2 stands for H or a free, esterified or etherified hydroxy group, with the proviso that at least one of the substituents R
and R2 is different from H; R3 stands for alkyl (1-4 C) and R4 ~ - 2 -stands for 0 or (X)(~Y), wherein X stands for H or aliphatic hydrocarbyl (1-4 C) and Y stands for a free, esterified or etherified hydroxy group; and the enantiomers and racemic mixtures thereof, characterized by treating a 13a,17a-epoxy steroid of the formula (9) R3"" ~
wherein Rl, R2 and R3 have the meanings given hereinbefore, with an acid to give a compound having the formula (1), wherein R4 stands for O, and, if required, the compound obtained is alkylated or reduced in 17-position~ any hydroxy group present is esterified or etherified and/or any ester group or ether group is hydrolyzed, and/or any racemate is resolved.
The group of new 8a compounds comprises not only the compounds with the natural configuration indicated above by the formula, but also the enantiomers thereof, and racemic mixtures.
The new ll-alkyl-8a-oestra-1,3,5(10)-trienes with formula I are valuable because of their oestrogenic, anti-oestrogenic, uterotropic and ovulation-inhibiting properties.
The new compounds exhibit especially an interesting dissociation between uterotropic and vaginotropic effect as compared with the 8a -compounds without lla-alkyl-substituent.
The following can also be stated as regards the 3 è
substituents Rl - R4:
Rl is preferably a hydroxy group, which may be esterified or etherified or not, for example hydroxy, hydrocarbyloxy(l-8 C), such as methoxy, ethoxy, cyclopentoxy, cyclohexenyloxy or benzyloxy;
trimethylsilyloxy; tetrahydropyranyloxy or carboxyacyloxy (1-7 C), such as acetoxy,propionoxy, pivaloyloxy or benzoyloxy. The highest preference for Rl is given to hydroxy, methoxy or acetoxy~
R2 is preferably H or identical with Rl.
R3 is preferably methyl or ethyl.
R4 is preferably (aX) (~OH) or (X) (~Oacetyl).
The aliphatic hydrocarbyl group possibly present in R4 and having 1-4 carbon atoms is a saturated or unsaturated hydrocarbon residue, e.g. methyl, ethyl, propyl, butyl isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, butynyl, propadienyl, or butadienyl. A preferred group is ethynyl.
An extremely suitable method of preparation is a biomi-metic total synthesis in accordance with a modified Johnson synthesis, where a suitable (Z)-olefinic polyene is stereo-selectively cyclized to a lla,17-di-alkyl-8a-gona-1,3,5(10),13(17)-tetraene. Epoxidizat-ion of the 13(17)-olefine obtained and opening up of the epoxide ring under weakly acid conditions gives rise to a migration - 3a -$
of the 17-alkyl group to position 13, whereby the corresponding 13~-alkyl-17-ketone forms.
The biomimetic total synthesis takes place in accordance with scheme A (see page 5), in which Rl, R2, R3 and R4 have the meanings already allocated A = 0 or P(R9)3, in which Rg = an aryl hydrocarbon group with 6 or 7 carbon atoms, preferably phenyl;
Z = 0 or P(Rg)3, in which Rg has the significance already allocated, on the understanding that Z = 0, when A = P(Rg)3 and conversely, whereby preferably A = P(Rg)3 and Z = 0;
R7 = H or CH3, and R8 = H or CH3, on the understanding that R8 = H if R7 CH3 and R8 ~ CH3 if R7 = H-R5 and/or R6 = hydroxy, hydrocarbyloxy (1-8 C), such as methoxy, ethoxy, cyclopentoxy, cyclohexenyl-oxy or benzyloxy; trimethylsilyloxy; tetrahydro-pyranyloxy; or carboxyacyloxy (1-7 C), such as acetoxy, propionoxy, pivaloyloxy or benzoyloxy.
R5 and/or R6 is preferably methoxy.
Reaction stage (a) is a Wittig reaction hetween an ylide (a phosphorane) and an aldehyde. During this reaction mainly the desired (Z) isomer (4) forms together with a small quantity (less than 10%) of the (E) isomer.
Reaction stage (b) takes place in a boiling acetic acid solution in the presence of a trace of sulphuric acid.
Reaction stage (c): The diketone (5) is cyclized with dilute base to give the cyclopentenone (6). In this stage the (E) isomer still present can best be removed, say by chromatography over silica gel.
The (E) isomer is somewhat more polar than the (Z) isomer.
Scheme A:
~C=A Z=C~ ( a)
FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS.
The invention relates to new 8a-oestra-1,3,5(10)-triene derivatives, processes for preparing these new 8a-steroids and to pharmaceutical compositions containing one or more of these new 8~-steroids as active constituent. The invention relates particularly to new 8a-oestra-1,3,5(10)-triene compounds having an 11-alkyl(1-4 C) substituent.
8a-steroids (or 8-iso-steroids) of the oestrane series are already known, see for example J~A.C.S. 80, 661 (1958); J.Med.Chem. 9, 338 (1966), Steroids 28, 325 (1976), U.S. patent 3 465 011.
A group of new 8a-oestra-1,3,5(10)-triene derivatives with interesting biological pro~perties has now been discovered, which is substituted at the lla-position by an alkyl group having 1-4 carbon atoms. The new 8a-compounds have the following ~ formula (1):
:
~ 20 1 ~ 1 3~
R3."
R
wherein Rl = H or a free, esterified or etherified hydroxy group R2 = H or a free, esterified or etherified hydroxy group, with the proviso that at least one of the substituents Rl and R2 is dissimilar to H
R3 = alkyl (1-4 C); and R4 = 0 or (X) (~Y), in which X = H or aliphatic hydrocarbyl (1=4 C) and Y = a free, esterified or etherified hydroxy group.
This invention also provides for a process for the preparation of novel 8a-oestra-1,3,5(10)-triene derivatives substituted at the lla-position by an alkyl group with 1-4 carbon atoms and have the formula (1):
r ~
wherein Rl stands for H or a free, esterified or etherified hydroxy group; R2 stands for H or a free, esterified or etherified hydroxy group, with the proviso that at least one of the substituents R
and R2 is different from H; R3 stands for alkyl (1-4 C) and R4 ~ - 2 -stands for 0 or (X)(~Y), wherein X stands for H or aliphatic hydrocarbyl (1-4 C) and Y stands for a free, esterified or etherified hydroxy group; and the enantiomers and racemic mixtures thereof, characterized by treating a 13a,17a-epoxy steroid of the formula (9) R3"" ~
wherein Rl, R2 and R3 have the meanings given hereinbefore, with an acid to give a compound having the formula (1), wherein R4 stands for O, and, if required, the compound obtained is alkylated or reduced in 17-position~ any hydroxy group present is esterified or etherified and/or any ester group or ether group is hydrolyzed, and/or any racemate is resolved.
The group of new 8a compounds comprises not only the compounds with the natural configuration indicated above by the formula, but also the enantiomers thereof, and racemic mixtures.
The new ll-alkyl-8a-oestra-1,3,5(10)-trienes with formula I are valuable because of their oestrogenic, anti-oestrogenic, uterotropic and ovulation-inhibiting properties.
The new compounds exhibit especially an interesting dissociation between uterotropic and vaginotropic effect as compared with the 8a -compounds without lla-alkyl-substituent.
The following can also be stated as regards the 3 è
substituents Rl - R4:
Rl is preferably a hydroxy group, which may be esterified or etherified or not, for example hydroxy, hydrocarbyloxy(l-8 C), such as methoxy, ethoxy, cyclopentoxy, cyclohexenyloxy or benzyloxy;
trimethylsilyloxy; tetrahydropyranyloxy or carboxyacyloxy (1-7 C), such as acetoxy,propionoxy, pivaloyloxy or benzoyloxy. The highest preference for Rl is given to hydroxy, methoxy or acetoxy~
R2 is preferably H or identical with Rl.
R3 is preferably methyl or ethyl.
R4 is preferably (aX) (~OH) or (X) (~Oacetyl).
The aliphatic hydrocarbyl group possibly present in R4 and having 1-4 carbon atoms is a saturated or unsaturated hydrocarbon residue, e.g. methyl, ethyl, propyl, butyl isopropyl, vinyl, propenyl, allyl, ethynyl, propynyl, propargyl, butynyl, propadienyl, or butadienyl. A preferred group is ethynyl.
An extremely suitable method of preparation is a biomi-metic total synthesis in accordance with a modified Johnson synthesis, where a suitable (Z)-olefinic polyene is stereo-selectively cyclized to a lla,17-di-alkyl-8a-gona-1,3,5(10),13(17)-tetraene. Epoxidizat-ion of the 13(17)-olefine obtained and opening up of the epoxide ring under weakly acid conditions gives rise to a migration - 3a -$
of the 17-alkyl group to position 13, whereby the corresponding 13~-alkyl-17-ketone forms.
The biomimetic total synthesis takes place in accordance with scheme A (see page 5), in which Rl, R2, R3 and R4 have the meanings already allocated A = 0 or P(R9)3, in which Rg = an aryl hydrocarbon group with 6 or 7 carbon atoms, preferably phenyl;
Z = 0 or P(Rg)3, in which Rg has the significance already allocated, on the understanding that Z = 0, when A = P(Rg)3 and conversely, whereby preferably A = P(Rg)3 and Z = 0;
R7 = H or CH3, and R8 = H or CH3, on the understanding that R8 = H if R7 CH3 and R8 ~ CH3 if R7 = H-R5 and/or R6 = hydroxy, hydrocarbyloxy (1-8 C), such as methoxy, ethoxy, cyclopentoxy, cyclohexenyl-oxy or benzyloxy; trimethylsilyloxy; tetrahydro-pyranyloxy; or carboxyacyloxy (1-7 C), such as acetoxy, propionoxy, pivaloyloxy or benzoyloxy.
R5 and/or R6 is preferably methoxy.
Reaction stage (a) is a Wittig reaction hetween an ylide (a phosphorane) and an aldehyde. During this reaction mainly the desired (Z) isomer (4) forms together with a small quantity (less than 10%) of the (E) isomer.
Reaction stage (b) takes place in a boiling acetic acid solution in the presence of a trace of sulphuric acid.
Reaction stage (c): The diketone (5) is cyclized with dilute base to give the cyclopentenone (6). In this stage the (E) isomer still present can best be removed, say by chromatography over silica gel.
The (E) isomer is somewhat more polar than the (Z) isomer.
Scheme A:
~C=A Z=C~ ( a)
(2) (3) R~f ~ (b)~
(4) (5) R~ Rs~ (e~
(6) (7) R ~ R~
(8) (9) R 1~ R 1~
(10) (1) 65 ~ `
It is not necessary to attempt complete removal, because small quantities of (E) isomer (less than 5%) do not deleteriously affect the subsequent progress of the synthesis.
Reaction stage (d) comprisis a reduction of the cyclopentenone (6) to the corresponding cyclo-pentenol (7) in the case where R7 = CH3 (and hence R8 = H).
The reduction of the cyclopentenone to the cyclopentenol is performed using a complex metal hydride such as lithium aluminium hydride, di-isobutyl-aluminiumhydride, sodium-di-isobutyl-boronhydride, at a temperature between -25 C and oo C.
If R7 = H then reaction stage (d) consists of Grignarding of the cyclopentenone (6) with methyl lithium or a methyl-magnesiumhalogenide which supplies the cyclopentenol (7), in which R7 = H
and R8 CH3.
The cyclization substrate (7) is cyclized ~reaction stage (e)) under acid conditions with the aid of a Lewis acid to give a ll-alkyl-8H-steroid (8).
During cyclization a protic or aprotic Lewis acid is employed and the reaction is carried out in a solvent which is preferably non-nucleophilic.
Examples of suitable solvents are formic acid, acetic acid, trifluoro acetic acid, trifluorethanol, nitroethane, benzene, saturated hydrocarbons such as pentane, hexane, cyclohexane and halogenated hydrocarbons such as dichloromethane.
Examples of protic Lewis acids are carbonic acids with a pK (20 C) ~4, preferably <2, such as for example formic acid, trifluoro-acetic acid, trichloro acetic acid. Examples of aprotic Lewis ~ ~ r~
acids are zinc chloride, zinc bromide, boron trifluoride. Preferably use is made of formic acid or zinc chloride, the amount being roughly 0.1 to 10 mol per mol cyclization substrate, preferably 0.5 to 5 mol per mol.
The cyclization reaction is normally carried out below room temperature (20-21 C) and above -150 C, preferably at a temperature between ~10 C and -100 C.
If in the starting product for cyclization R5~R6 (e.g. R5 = methoxy and R6 = H or conversely), then during cyclization two position-isomers can form. The ratio thereof can be influenced by the reaction conditions and by the choice of the substituents R5 and R6. If for example R5 = methoxy and R6 = H, then a "para-"product (Rl = methoxy, R2 = H) and an "ortho" product ~Rl = H, R2 = methoxy) can form. Normally more "para" product forms than "ortho" product. In this manner we thus obtain a steroid which is substituted at the 3-position, in addition to a steroid substituted at the l-position.
Separation of these two products can be undertaken in the normal way, e.g. by chromatography. The separate products can be further purified by crystallisation, e.g. from methanol. If R5 - R6, then during cyclization only one product forms, a 1,3-di-substituted steroid.
In reaction stage (f) the 13,17 double bond is epoxidized in the cyclization product (8]. Epoxidation with a peroxy acid in this case supplies mainly the desired a-epoxide (9). A suitable peroxy acid is for example m-chloroperbenzoic acid. The ~-epoxide formed during epoxidation, usually less than 10%, can be separated from the ~-epoxide by column chromatography over deactivated alumina.
1:~ ,3~
The lla-alkyl-8~-gona-1,3,5(10),13t17)-tetraenes (8) obtained during cyclization, and the 13a,17a-epoxy derivatives obtained therefrom are also new compounds with blological activity and are at the same time important intermediate products for the preparation of the new biologically active lla-alkyl-8a-steroids (1) .
During reaction stage (g) the a-epoxide (9), by treatment with an acid, preferably aprotic lewis acid such as borontrifluoride-etherate, in a suitable solvent for example toluene, at a temperature between -100 C and 80 C, preferably between -40 C and 20 C, is converted into the 8~-oestrone derivative ( 10) .
The 8a-oestrone derivative (10) obtained in this manner appertains to the group of new lla-alkyl-8-oestra-1,3,5(10)-trienes of the present invention.
In this 8a-oestrone derivative (10) it is possible in a known manner to introduce other substituents at position 17 (reaction stage h). If required the substituents in the A-ring (Rl and R2) can also be modified by splitting off (hydrolysis) of ester or ether groups and/or esterification or etherification of hydroxy groups.
A 17-oxo ~roup can if required be reduced to a 17~-hydroxy group, e.g. with a complex metal hydride such as lithium aluminium hydride.
The introduction of a saturated or unsaturated hydrocarbon group at position 17 is undertaken by reacting the 17-oxo steroid with a metal derivative of a saturated or unsaturated aliphatic hydrocarbon, possibly followed by a reduction of the side chains thus introducedO The metal derivative can be a Grignard compound, e.g. the magnesium bromide of the appropriate hydrocarbon, or an alkyl lithium compound.
A particular embodiment of the condensation reaction for the preparation of the 17~-hydroxy-17a-alkynyl compounds consists in reacting the 17-oxo steroid with a triply unsaturated hydrocarbon, e.g.
acetylene, in the presence of an alkali metal or an alkali m~tal compound, such as an alkali metal amide or alcoholate, or with a metal compound of a triply unsaturated hydrocarbon such as an al~ali metal or earth alkali metal compound, e.g. potassium acetylide.
The ester group possibly present in the end products at positions 1, 3 and/or 17 can be derived from a saturated or unsaturated organic carboxylic acid with 1-18 carbon atoms. The conversion of a hydroxy group into an ester group can take place in accordance with a known method, e.g. by reacting the hydroxy steroid with the appropriate acid or a functional derivative thereof, such as the anhydride or the halogenide. The esterification of the 17~-hydroxy group, which is formed during the 17-alkylation, can also take place by allowing the reaction product of the condensation of the 17-oxo steroid with a metal derivative of an unsaturated hydrocarbon residue, to react without prior hydrolysis with the corresponding acid or a functional derivative thereof. Esterification can for example also take place by allowing the steroid to react with a carboxylic acid anhydride such as acetic acid anhydride in the presence of 4-dimethyl aminopyridine, preferably at the same time in the presence of a tertiary amine such as trimethyl amine.
As examples of organic carboxylic acids which can be employed for esterification the following are mentioned: formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caprinic acid, undecylic ~ r! 3 ~ ~ .
acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, oleic acid, palmitic acid, stearic acid, adamantane carboxylic acid, trimethyl acetic acid, diethyl acetic acid, cyclohexylpropionlc acid, undecylenic acid, benzoic acid, phenyl acetic acid, phenyl propionic acid,- phenyl butyric acid, fumaric acid, malonic acid, succinic acid, glutaric acid, pimelic acid, and tartaric acid. As already stated it is also possible to use functional derivatives thereof such as the anhydrides or acid chlorides.
The ether groups present in the end products at positions 1, 3 and/or 17 can be derived from an aliphatic, aromatic, araliphatic or heterocyclic hydrocarbon. Examples of such ether groups are the methyl ether, ethyl ether, butyl ether, cyclopentyl ether, tetrahydropyranyl ether, cyclohexyl ether and l'-ethoxyethyl ether group.
Etherification can take place in accordance with standard methods.
The cyclopentonol (7) to be cyclized contains two chiral centres, namely the carbon atom which bears the substituent R8 and the carbon atom which bears the substituent R3. The stereo-chemistry of the cyclization product appears now to be governed mainly by the latter-mentioned centre. If we take as a basis a racemic mixture, then a racemic tetra-cyclic product appears to form consisting of 2 enan-tiomers, whilst because of the two chiral centres without optical induction, four stereo isomers in equal quantities should have formed. That the chiral centre in the cyclopentanol group hardly has any influence on the stereo chemistry of the cyclization product is indicated by the fact that the (S)-OH-(R)-R3-substituted starting product gives the same 6 5 ~
lla-R3-substituted cyclization product as the (R)-OH-(R)-R3-substituted starting product.
If an optically active starting prodùct is taken as a basis, e.g. the (R)-R3 cyclopentenol, S then an optically active cycli7ation product (9) is formed, e.g. a natural lla-8a gona-1,3,5,13(17)-tetraene.
Racemic mixtures of intermediates or end products can be separated in the normal way into the optical antipodes, e.g. by reaction of the dl-steroid or a derivative thereof with an optically active acid or base, fractional crystallization or chromatography of the reaction product to obtain optically pure compounds and hydrolysis to give the pure d- and/or l-steroid.
The new compounds according to the invention may be used in the form of pharmaceutical compositions, for which purpose an effective amount thereof is mixed with one or more pharmaceutically acceptable non-toxic carriers and/or the usual excipients suitable for enteral or parenteral administration.
The invention will now be explained with the aid of the following examples.
.
Example 1 a) dl-2-Meth~-4-(S-meth~l-?-furYl)-butane nitrile solution of 2-(3-bromobutyl)-5-methyl-~uran (20.5 g) and 13 g KCN in 100 ml of dry dimethyl sulphoxide was heated during stirring for 16 hours at 50-55 C. The mixture was cooled, diluted with water and extracted using ether. The extracts were washed with wa~er, dried on anhydrous MgS04 and boiled down under vacuum. The residue was sub~ected to chromatographic adsorption over silicagel with hexane/ethyl acetate (9:1) and gave 14.6 g dl-2-methyl-4-(S-methyl-2-furyl)-butane nitrile.
~ ti. ~?~S5 ~
This product can also be prepared starting from 4-(5-methyl-2-furyl)-butane nitrile by alkylation with methyl iodide in the presence of lithium diethyl amide in a manner similar to that described in example Va.
b) dl-2-Methyl-4-(5-methyl-2-furyl)-butanal (formula (3): R3 = R7 = methyl, Z = 0) 42 ml of 1,2 M di-i50butyl aluminium hydride solution in toluene was added dropwise to a solution of 8.15 g (0.05 mol) 2-methyl-4-(5-methyl-2-furyl)-butane nitrile in 250 ml dry toluene, which had been cooled down to -78 C, during stirring and under nitrogen. The solution obtained was stirred for 30 minutes at -70 C and then poured into excess 2 N hydrochloric acid. The organic layer was separated and then washed successively with 2 N
hydrochloric acid, water and sodium bicarbonate solution. The resultant solution was dried on anhydrous sodium sulphate and concentrated under reduced pressure. In this way 5.4 g (65% yield) of the desired butanal (content >90%) was obtained which without further purification was used in the Wittig reaction from example Ic).
c) dl-(Z)-1-(3-methoxxphenyl)-5-methvl-7-(s-methyl-2 furYl)-3-heptene (formula (4), R3 = R7 = CH3, R5 # methoxy, R6 ~ H) A suspension of 49.1 9 (0.10 mol) 3-(3-methoxy-phenyl)propyl-triphenyl phosphonium bromide in 200 ml dry tetrahydrofurane was treated under nitrogen at 30 0-5 C with 62 ml 1.62 M (0~10 ml) n-butyl lithium solution in hexane. The red solution obtained was stirred for 15 minutes, after which 15.0 9 (90 mmol) dl-2-methyl-4-(5-methyl-2-furyl)-butanal dissolved in 50 ml dry tetrahydrofurane was added dropwise during stirring at 0-5 C. The reaction mixture was ~ -~ 7`~
mixed with water and extracted using ether (3x).
The extracts were washed with water, dried on anhydrous sodium sulphate and concentrated under reduced pressure. The residue was subjected to chromatography above 200 g silicagel with hexane/
ethyl acetate 9:1. This gave 19.6 g (73X yield) product with a content of 93X of the desired (z)-isomer.
d) dl-2-r(Z)-6-(3-methoxyphenyl)-2-methYl-3-hexenyll-
(4) (5) R~ Rs~ (e~
(6) (7) R ~ R~
(8) (9) R 1~ R 1~
(10) (1) 65 ~ `
It is not necessary to attempt complete removal, because small quantities of (E) isomer (less than 5%) do not deleteriously affect the subsequent progress of the synthesis.
Reaction stage (d) comprisis a reduction of the cyclopentenone (6) to the corresponding cyclo-pentenol (7) in the case where R7 = CH3 (and hence R8 = H).
The reduction of the cyclopentenone to the cyclopentenol is performed using a complex metal hydride such as lithium aluminium hydride, di-isobutyl-aluminiumhydride, sodium-di-isobutyl-boronhydride, at a temperature between -25 C and oo C.
If R7 = H then reaction stage (d) consists of Grignarding of the cyclopentenone (6) with methyl lithium or a methyl-magnesiumhalogenide which supplies the cyclopentenol (7), in which R7 = H
and R8 CH3.
The cyclization substrate (7) is cyclized ~reaction stage (e)) under acid conditions with the aid of a Lewis acid to give a ll-alkyl-8H-steroid (8).
During cyclization a protic or aprotic Lewis acid is employed and the reaction is carried out in a solvent which is preferably non-nucleophilic.
Examples of suitable solvents are formic acid, acetic acid, trifluoro acetic acid, trifluorethanol, nitroethane, benzene, saturated hydrocarbons such as pentane, hexane, cyclohexane and halogenated hydrocarbons such as dichloromethane.
Examples of protic Lewis acids are carbonic acids with a pK (20 C) ~4, preferably <2, such as for example formic acid, trifluoro-acetic acid, trichloro acetic acid. Examples of aprotic Lewis ~ ~ r~
acids are zinc chloride, zinc bromide, boron trifluoride. Preferably use is made of formic acid or zinc chloride, the amount being roughly 0.1 to 10 mol per mol cyclization substrate, preferably 0.5 to 5 mol per mol.
The cyclization reaction is normally carried out below room temperature (20-21 C) and above -150 C, preferably at a temperature between ~10 C and -100 C.
If in the starting product for cyclization R5~R6 (e.g. R5 = methoxy and R6 = H or conversely), then during cyclization two position-isomers can form. The ratio thereof can be influenced by the reaction conditions and by the choice of the substituents R5 and R6. If for example R5 = methoxy and R6 = H, then a "para-"product (Rl = methoxy, R2 = H) and an "ortho" product ~Rl = H, R2 = methoxy) can form. Normally more "para" product forms than "ortho" product. In this manner we thus obtain a steroid which is substituted at the 3-position, in addition to a steroid substituted at the l-position.
Separation of these two products can be undertaken in the normal way, e.g. by chromatography. The separate products can be further purified by crystallisation, e.g. from methanol. If R5 - R6, then during cyclization only one product forms, a 1,3-di-substituted steroid.
In reaction stage (f) the 13,17 double bond is epoxidized in the cyclization product (8]. Epoxidation with a peroxy acid in this case supplies mainly the desired a-epoxide (9). A suitable peroxy acid is for example m-chloroperbenzoic acid. The ~-epoxide formed during epoxidation, usually less than 10%, can be separated from the ~-epoxide by column chromatography over deactivated alumina.
1:~ ,3~
The lla-alkyl-8~-gona-1,3,5(10),13t17)-tetraenes (8) obtained during cyclization, and the 13a,17a-epoxy derivatives obtained therefrom are also new compounds with blological activity and are at the same time important intermediate products for the preparation of the new biologically active lla-alkyl-8a-steroids (1) .
During reaction stage (g) the a-epoxide (9), by treatment with an acid, preferably aprotic lewis acid such as borontrifluoride-etherate, in a suitable solvent for example toluene, at a temperature between -100 C and 80 C, preferably between -40 C and 20 C, is converted into the 8~-oestrone derivative ( 10) .
The 8a-oestrone derivative (10) obtained in this manner appertains to the group of new lla-alkyl-8-oestra-1,3,5(10)-trienes of the present invention.
In this 8a-oestrone derivative (10) it is possible in a known manner to introduce other substituents at position 17 (reaction stage h). If required the substituents in the A-ring (Rl and R2) can also be modified by splitting off (hydrolysis) of ester or ether groups and/or esterification or etherification of hydroxy groups.
A 17-oxo ~roup can if required be reduced to a 17~-hydroxy group, e.g. with a complex metal hydride such as lithium aluminium hydride.
The introduction of a saturated or unsaturated hydrocarbon group at position 17 is undertaken by reacting the 17-oxo steroid with a metal derivative of a saturated or unsaturated aliphatic hydrocarbon, possibly followed by a reduction of the side chains thus introducedO The metal derivative can be a Grignard compound, e.g. the magnesium bromide of the appropriate hydrocarbon, or an alkyl lithium compound.
A particular embodiment of the condensation reaction for the preparation of the 17~-hydroxy-17a-alkynyl compounds consists in reacting the 17-oxo steroid with a triply unsaturated hydrocarbon, e.g.
acetylene, in the presence of an alkali metal or an alkali m~tal compound, such as an alkali metal amide or alcoholate, or with a metal compound of a triply unsaturated hydrocarbon such as an al~ali metal or earth alkali metal compound, e.g. potassium acetylide.
The ester group possibly present in the end products at positions 1, 3 and/or 17 can be derived from a saturated or unsaturated organic carboxylic acid with 1-18 carbon atoms. The conversion of a hydroxy group into an ester group can take place in accordance with a known method, e.g. by reacting the hydroxy steroid with the appropriate acid or a functional derivative thereof, such as the anhydride or the halogenide. The esterification of the 17~-hydroxy group, which is formed during the 17-alkylation, can also take place by allowing the reaction product of the condensation of the 17-oxo steroid with a metal derivative of an unsaturated hydrocarbon residue, to react without prior hydrolysis with the corresponding acid or a functional derivative thereof. Esterification can for example also take place by allowing the steroid to react with a carboxylic acid anhydride such as acetic acid anhydride in the presence of 4-dimethyl aminopyridine, preferably at the same time in the presence of a tertiary amine such as trimethyl amine.
As examples of organic carboxylic acids which can be employed for esterification the following are mentioned: formic acid, acetic acid, propionic acid, butyric acid, valeric acid, caprinic acid, undecylic ~ r! 3 ~ ~ .
acid, lauric acid, tridecylic acid, myristic acid, pentadecylic acid, oleic acid, palmitic acid, stearic acid, adamantane carboxylic acid, trimethyl acetic acid, diethyl acetic acid, cyclohexylpropionlc acid, undecylenic acid, benzoic acid, phenyl acetic acid, phenyl propionic acid,- phenyl butyric acid, fumaric acid, malonic acid, succinic acid, glutaric acid, pimelic acid, and tartaric acid. As already stated it is also possible to use functional derivatives thereof such as the anhydrides or acid chlorides.
The ether groups present in the end products at positions 1, 3 and/or 17 can be derived from an aliphatic, aromatic, araliphatic or heterocyclic hydrocarbon. Examples of such ether groups are the methyl ether, ethyl ether, butyl ether, cyclopentyl ether, tetrahydropyranyl ether, cyclohexyl ether and l'-ethoxyethyl ether group.
Etherification can take place in accordance with standard methods.
The cyclopentonol (7) to be cyclized contains two chiral centres, namely the carbon atom which bears the substituent R8 and the carbon atom which bears the substituent R3. The stereo-chemistry of the cyclization product appears now to be governed mainly by the latter-mentioned centre. If we take as a basis a racemic mixture, then a racemic tetra-cyclic product appears to form consisting of 2 enan-tiomers, whilst because of the two chiral centres without optical induction, four stereo isomers in equal quantities should have formed. That the chiral centre in the cyclopentanol group hardly has any influence on the stereo chemistry of the cyclization product is indicated by the fact that the (S)-OH-(R)-R3-substituted starting product gives the same 6 5 ~
lla-R3-substituted cyclization product as the (R)-OH-(R)-R3-substituted starting product.
If an optically active starting prodùct is taken as a basis, e.g. the (R)-R3 cyclopentenol, S then an optically active cycli7ation product (9) is formed, e.g. a natural lla-8a gona-1,3,5,13(17)-tetraene.
Racemic mixtures of intermediates or end products can be separated in the normal way into the optical antipodes, e.g. by reaction of the dl-steroid or a derivative thereof with an optically active acid or base, fractional crystallization or chromatography of the reaction product to obtain optically pure compounds and hydrolysis to give the pure d- and/or l-steroid.
The new compounds according to the invention may be used in the form of pharmaceutical compositions, for which purpose an effective amount thereof is mixed with one or more pharmaceutically acceptable non-toxic carriers and/or the usual excipients suitable for enteral or parenteral administration.
The invention will now be explained with the aid of the following examples.
.
Example 1 a) dl-2-Meth~-4-(S-meth~l-?-furYl)-butane nitrile solution of 2-(3-bromobutyl)-5-methyl-~uran (20.5 g) and 13 g KCN in 100 ml of dry dimethyl sulphoxide was heated during stirring for 16 hours at 50-55 C. The mixture was cooled, diluted with water and extracted using ether. The extracts were washed with wa~er, dried on anhydrous MgS04 and boiled down under vacuum. The residue was sub~ected to chromatographic adsorption over silicagel with hexane/ethyl acetate (9:1) and gave 14.6 g dl-2-methyl-4-(S-methyl-2-furyl)-butane nitrile.
~ ti. ~?~S5 ~
This product can also be prepared starting from 4-(5-methyl-2-furyl)-butane nitrile by alkylation with methyl iodide in the presence of lithium diethyl amide in a manner similar to that described in example Va.
b) dl-2-Methyl-4-(5-methyl-2-furyl)-butanal (formula (3): R3 = R7 = methyl, Z = 0) 42 ml of 1,2 M di-i50butyl aluminium hydride solution in toluene was added dropwise to a solution of 8.15 g (0.05 mol) 2-methyl-4-(5-methyl-2-furyl)-butane nitrile in 250 ml dry toluene, which had been cooled down to -78 C, during stirring and under nitrogen. The solution obtained was stirred for 30 minutes at -70 C and then poured into excess 2 N hydrochloric acid. The organic layer was separated and then washed successively with 2 N
hydrochloric acid, water and sodium bicarbonate solution. The resultant solution was dried on anhydrous sodium sulphate and concentrated under reduced pressure. In this way 5.4 g (65% yield) of the desired butanal (content >90%) was obtained which without further purification was used in the Wittig reaction from example Ic).
c) dl-(Z)-1-(3-methoxxphenyl)-5-methvl-7-(s-methyl-2 furYl)-3-heptene (formula (4), R3 = R7 = CH3, R5 # methoxy, R6 ~ H) A suspension of 49.1 9 (0.10 mol) 3-(3-methoxy-phenyl)propyl-triphenyl phosphonium bromide in 200 ml dry tetrahydrofurane was treated under nitrogen at 30 0-5 C with 62 ml 1.62 M (0~10 ml) n-butyl lithium solution in hexane. The red solution obtained was stirred for 15 minutes, after which 15.0 9 (90 mmol) dl-2-methyl-4-(5-methyl-2-furyl)-butanal dissolved in 50 ml dry tetrahydrofurane was added dropwise during stirring at 0-5 C. The reaction mixture was ~ -~ 7`~
mixed with water and extracted using ether (3x).
The extracts were washed with water, dried on anhydrous sodium sulphate and concentrated under reduced pressure. The residue was subjected to chromatography above 200 g silicagel with hexane/
ethyl acetate 9:1. This gave 19.6 g (73X yield) product with a content of 93X of the desired (z)-isomer.
d) dl-2-r(Z)-6-(3-methoxyphenyl)-2-methYl-3-hexenyll-
3-methyl-2-cvcloPentonone (formula (6), R3 = R7 =
CH3, R5 = methoxy, R6 = H) The Wittig product from example Ic) (14.9 g, 50 mmol) was mixed with 660 ml acetic acid, 330 ml water and 15 ml of 4 N sulphuric acid. The mixture was boiled for 3 hours sub~ect to reflux cooling, and then cooled down and mixed with 1 litre water.
The mixture obtained was extracted using 4 portions of 150 ml dichloromethane. The extracts were merged, washed with water (3x) and sodium bicarbonate solution, and dried on anhydrous potassium carbonate.
The solvent was evaporated under reduced pressure and the residue was put into 400 ml ethanol. A
solution of 3.3 g KOH in 200 ml water was added and the mixture obtained was boiled for 4 hours under reflux cooling. The reaction mixture was cooled and, under reduced pressure, was concentrated to roughly one third of the original volume. Extraction was then undertaken using 3 portions of ethyl acetate, which was subsequently washed with water and dried on anhydrous sodium sulphate. The solvent was evaporated off and the residue obtained was subjected to chromatography above 300 g silicagel with hexane/
ethyl acetate 8:2. Initially 11.0 g (74% yield) of substance was isolated having a content of roughly 95X of the desired product. Further elution gave a t ~ 7~i; t further 1.2 g (8% yield) of product contaminated with (E) isomer.
e) dl-l- and dl-3-methoxy-lla,17-dimethyl-8~-qona-1,3,5(10),13(17)-tetraene (formula (8), R3 =
CH3, Rl = H, R2 = methoxy or Rl = methoxy, R2 = H) At -20 C 0.38 g (10 mmol) of lithium aluminium anhydride was added slowly to a solution o~ cyclo-pentenone from example Id) (3.0 g, 10 mmol) in 100 ml of dry ether. The mixture was heated during stirring for about 30 minutes to 0 C, after which saturated sodium sulphate solution was carefully added dropwise. The ether laywer was decanted off from the resultant deposit, which was subsequently extracted twice again using dry ether. The merged ether layers were concentrated. The residue (cyclopentenol (7), in which R3 = R7 = CH3, R5 =
methoxy, R6 = H, R8 = H) was dissolved in 50 ml nitro ethane and, during stirring, was added dropwise to a mixture of 5.45 g (40 mmol) zinc chloride and 200 ml nitro ethane whlch had been cooled down to -35 C. After a further 10 minutes stirring at -35 C
the reaction mixture was poured in~o water and extracted wlth ether. The extracts were washed with water, dried on anhydrous sodium sulphate, and 25 ~ concentrated under reduced pressure. The residue was sub~ected to chromatography above 90 g silicagel with hexane/toluene 8:2. Initially the l-methoxy isomer was eluated (0.874 g, 31% yield), followed by the 3-methoxy isomer (1.52 g, 54~ yield).
30 Recrystallisation from methanol gave 0.79 g (2816 yield) of pure l-methoxy isomer, melting point 77.5 - 78 C, and 1.27 g (45% yield) pure 3-methoxy isomer, melting point 74 - 75 C.
I1.~6~
Example II
a) dl-3-methoxy-lla,17-dimethvl-13a~17-epoxy-8-qona-1,3,5(10)-triene (formule (9), Rl = methoxy, R2 = ~, R3 = methyl) A solution of 1.41 g (5 mmol) of the 3-methoxy isomer from example I was dissolved in 80 ml dichloromethane. The solution was cooled down to -30 C and a solution of 1.48 g m-chloroperbenzoic acid (content 70%, 1.2 equiv.) in 20 ml dichloro-methane was added slowly dropwise. The reaction mixture obtained was stirred for 15 minutes at -20 C
to -10 C and then washed with potassium carbonate solution, dried on anhydrous potassium carbonate and concentrated. The residue was recrystallised from hexane. This gave 1.12 g (75% yield) of the desired epoxide, melting point 148-151 C.
b) dl-lla-methyl-8-oestrone methvl ether (formula (10), Rl = methoxy, R2 = H, R3 a methyl) A solution of 0.894 g (3 mmol) of the epoxide from example IIa) in 70 ml toluene was cooled under nitrogen to -40 C. Then during stirring 2 ml of borotrifluoride-ethanol was added and the red solution obtained was heated for about 30 minutes to -10 C.
The reaction mixture was shaken with an aqueous potassium carbonate solution until colourless. The organic layer was separated out, dried on anhydrous potassium carbonate and boiled down. The residue was sub~ected to chromatography above 50 9 silicagel with hexane/ethyl acetate 95:5 - 90:10. 0.322 9 (36% yield) dl~ methyl-8-oestrone methyl ether was lsolated, melting point 136-137.5 C (from ether/hexane).
~ ~'7~5:~ `
Example III
dl-lla-Meth 1-8a-oestradiol 3-methYl ether (formula Y _ _ (1): Rl = methoxy, R2 = H, R3 = methyl, R4 = H(~OH)) 0.10 g (2.6 mmol) of lithium aluminium hydride was added to a solution of 0.45 9 (1.5 mmol) of the 8a-oestrone derivative from example II in 20 ml toluene/ether 1:1.
The mixture was stirred for 30 minutes at room temperature and subsequently processed in the manner described in example Ie). The crude product was sub~ected to chromatography above 15 9 silicagel with hexane/ethyl acetate 8:2 and recrystallised from ether. In thic way 0.36 g (80% yield) dl-lla-methyl-8a-oestradiol 3-methyl ether was obtained, 15 melting point 129-130.5 C.
E~ le IV
dl-lla-MethYl-8a-oestradiol tformula (1): Rl = OH, R2 = H, R3 = methyl, R4 = H(~OH)) A mixture of 0.36 9 (1.2 mmol) dl-lla-methyl-8a-oestradiol 3-methyl ether and 2.5 9 pyridine hydrochloride was heated for 1 hour to 200 C. After cooling the reaction mixture was mixed with water and extracted with 3 portions of ethyl acetate. The extracts were washed with water, dried in anhydrous sodium sulphate and concentrated. The residue was filtered over silicagel with ethyl acetate.
Concentration and recrystallisation from ether gave 0.285 g (83% yield) dl-lla-methyl-8a-oestradiol, melting point 219-221 C.
3 ~ ~ ~
Example V
a) dl-2-Ethy1-4-(5-methYl-2-furyl)-butane nitrile A solution of lithium diethyl amide prepared from 0.7 9 (0.1 mol) lithium and 7.3 9 (0.1 mol) diethyl amine in 44 ml benzene/hexamethyl phosphoric acid triamide l:l (2 hours at 25 C) was added dropwise under nitrogen to a mixture which had been cooled down to -70 C of 14.9 9 (0.1 mol)
CH3, R5 = methoxy, R6 = H) The Wittig product from example Ic) (14.9 g, 50 mmol) was mixed with 660 ml acetic acid, 330 ml water and 15 ml of 4 N sulphuric acid. The mixture was boiled for 3 hours sub~ect to reflux cooling, and then cooled down and mixed with 1 litre water.
The mixture obtained was extracted using 4 portions of 150 ml dichloromethane. The extracts were merged, washed with water (3x) and sodium bicarbonate solution, and dried on anhydrous potassium carbonate.
The solvent was evaporated under reduced pressure and the residue was put into 400 ml ethanol. A
solution of 3.3 g KOH in 200 ml water was added and the mixture obtained was boiled for 4 hours under reflux cooling. The reaction mixture was cooled and, under reduced pressure, was concentrated to roughly one third of the original volume. Extraction was then undertaken using 3 portions of ethyl acetate, which was subsequently washed with water and dried on anhydrous sodium sulphate. The solvent was evaporated off and the residue obtained was subjected to chromatography above 300 g silicagel with hexane/
ethyl acetate 8:2. Initially 11.0 g (74% yield) of substance was isolated having a content of roughly 95X of the desired product. Further elution gave a t ~ 7~i; t further 1.2 g (8% yield) of product contaminated with (E) isomer.
e) dl-l- and dl-3-methoxy-lla,17-dimethyl-8~-qona-1,3,5(10),13(17)-tetraene (formula (8), R3 =
CH3, Rl = H, R2 = methoxy or Rl = methoxy, R2 = H) At -20 C 0.38 g (10 mmol) of lithium aluminium anhydride was added slowly to a solution o~ cyclo-pentenone from example Id) (3.0 g, 10 mmol) in 100 ml of dry ether. The mixture was heated during stirring for about 30 minutes to 0 C, after which saturated sodium sulphate solution was carefully added dropwise. The ether laywer was decanted off from the resultant deposit, which was subsequently extracted twice again using dry ether. The merged ether layers were concentrated. The residue (cyclopentenol (7), in which R3 = R7 = CH3, R5 =
methoxy, R6 = H, R8 = H) was dissolved in 50 ml nitro ethane and, during stirring, was added dropwise to a mixture of 5.45 g (40 mmol) zinc chloride and 200 ml nitro ethane whlch had been cooled down to -35 C. After a further 10 minutes stirring at -35 C
the reaction mixture was poured in~o water and extracted wlth ether. The extracts were washed with water, dried on anhydrous sodium sulphate, and 25 ~ concentrated under reduced pressure. The residue was sub~ected to chromatography above 90 g silicagel with hexane/toluene 8:2. Initially the l-methoxy isomer was eluated (0.874 g, 31% yield), followed by the 3-methoxy isomer (1.52 g, 54~ yield).
30 Recrystallisation from methanol gave 0.79 g (2816 yield) of pure l-methoxy isomer, melting point 77.5 - 78 C, and 1.27 g (45% yield) pure 3-methoxy isomer, melting point 74 - 75 C.
I1.~6~
Example II
a) dl-3-methoxy-lla,17-dimethvl-13a~17-epoxy-8-qona-1,3,5(10)-triene (formule (9), Rl = methoxy, R2 = ~, R3 = methyl) A solution of 1.41 g (5 mmol) of the 3-methoxy isomer from example I was dissolved in 80 ml dichloromethane. The solution was cooled down to -30 C and a solution of 1.48 g m-chloroperbenzoic acid (content 70%, 1.2 equiv.) in 20 ml dichloro-methane was added slowly dropwise. The reaction mixture obtained was stirred for 15 minutes at -20 C
to -10 C and then washed with potassium carbonate solution, dried on anhydrous potassium carbonate and concentrated. The residue was recrystallised from hexane. This gave 1.12 g (75% yield) of the desired epoxide, melting point 148-151 C.
b) dl-lla-methyl-8-oestrone methvl ether (formula (10), Rl = methoxy, R2 = H, R3 a methyl) A solution of 0.894 g (3 mmol) of the epoxide from example IIa) in 70 ml toluene was cooled under nitrogen to -40 C. Then during stirring 2 ml of borotrifluoride-ethanol was added and the red solution obtained was heated for about 30 minutes to -10 C.
The reaction mixture was shaken with an aqueous potassium carbonate solution until colourless. The organic layer was separated out, dried on anhydrous potassium carbonate and boiled down. The residue was sub~ected to chromatography above 50 9 silicagel with hexane/ethyl acetate 95:5 - 90:10. 0.322 9 (36% yield) dl~ methyl-8-oestrone methyl ether was lsolated, melting point 136-137.5 C (from ether/hexane).
~ ~'7~5:~ `
Example III
dl-lla-Meth 1-8a-oestradiol 3-methYl ether (formula Y _ _ (1): Rl = methoxy, R2 = H, R3 = methyl, R4 = H(~OH)) 0.10 g (2.6 mmol) of lithium aluminium hydride was added to a solution of 0.45 9 (1.5 mmol) of the 8a-oestrone derivative from example II in 20 ml toluene/ether 1:1.
The mixture was stirred for 30 minutes at room temperature and subsequently processed in the manner described in example Ie). The crude product was sub~ected to chromatography above 15 9 silicagel with hexane/ethyl acetate 8:2 and recrystallised from ether. In thic way 0.36 g (80% yield) dl-lla-methyl-8a-oestradiol 3-methyl ether was obtained, 15 melting point 129-130.5 C.
E~ le IV
dl-lla-MethYl-8a-oestradiol tformula (1): Rl = OH, R2 = H, R3 = methyl, R4 = H(~OH)) A mixture of 0.36 9 (1.2 mmol) dl-lla-methyl-8a-oestradiol 3-methyl ether and 2.5 9 pyridine hydrochloride was heated for 1 hour to 200 C. After cooling the reaction mixture was mixed with water and extracted with 3 portions of ethyl acetate. The extracts were washed with water, dried in anhydrous sodium sulphate and concentrated. The residue was filtered over silicagel with ethyl acetate.
Concentration and recrystallisation from ether gave 0.285 g (83% yield) dl-lla-methyl-8a-oestradiol, melting point 219-221 C.
3 ~ ~ ~
Example V
a) dl-2-Ethy1-4-(5-methYl-2-furyl)-butane nitrile A solution of lithium diethyl amide prepared from 0.7 9 (0.1 mol) lithium and 7.3 9 (0.1 mol) diethyl amine in 44 ml benzene/hexamethyl phosphoric acid triamide l:l (2 hours at 25 C) was added dropwise under nitrogen to a mixture which had been cooled down to -70 C of 14.9 9 (0.1 mol)
4-(5-methyl-2-furyl)-butane nitrile, 15.6 9 (0.1 mol) ethyl iodide, 20 ml dry tetrahydrofurane and 140 ml dry ether. The mixture obtained was stirred for one hour at -70 C, was slowly heated up to 10 C
and then poured into cold water. The organic layer was separated off, washed with water and dried on anhydrous magnesium sulphate. The solvent was evaporated off under reduced pressure and the residue was sub~ected to chromatography over 300 9 silicagel with hexane/ethyl acetate 95:5. Initially 2.3 g dl-2,2-diethyl-4-(5-methyl-2-furyl)-butane nitrile was eluated, followed by 9.5 9 (58% yield) dl-2-ethyl-4-(5-methyl-2-furyl)-butane nitrile.
b~ dl-2-Ethy_-4-(5-methY1-2-furyl)-butanal (formula (3): R3 = ethyl, R7 = methyl, Z = 0~
The product from example Va) was reduced in a manner analogous to that described in example Ib) to the corresponding aldehyde, with 49% yield.
c) dl-2-r(Z)-6-(3-methoxvphenyl)-2-ethyl-hexenyll-3-meth~1-2-c~cloPentenone ~formula (6), R3 ~ C2H5, R7 = CH3, R5 = methoxy, R6 = H) The product from example Ib) was subjected to a Wittig reaction as de~cribed in example Ic) and then converted to the cyclopentenone derivative mentioned in the preamble, in a manner similar to that described in example Id). These reactions gave an overall yield of 62%.
i ~ 7 ~
d) dl-l- and dl-3-methoxy-lla-ethyl-17-methyl-8~-qona-1,3,5(10),13(17)-tetraene (formula (8), R3 = C2H5, Rl = H, R2 = methoxy or Rl = methoxy, R2 = H) S The cyclopentenone from example Vd) was reduced and cyclized in a manner analogous to that described in example Ie). The l-methoxy isomer was isolated, with 12% yield, melting point 107-108 C
(recrystallisation from methanol) and the 3-methoxy isomer with 43.6% yield, melting point 89-90 C
(from methanol).
Example VI
dl-lla-EthYl-8a-oestrone methYl ether (formula (10), Rl = methoxy, R2 ~ H~ R3 = C2H5) The 3-methoxy isomer from example Vd) was oxidised and reacted in a manner analogous to that described in example II. In this way dl-lla-ethyl-8a-oestrone methyl ether was obtained with 25% yield (oil).
Example VII
dl-lla-Ethyl-8a-oestradiol (formula (1): Rl = OH, R2 = H, R3 = ethyl, R4 = H(~OH)) The oestrone derivative from example VI was reduced and demethylated in the manner as described in examples III and IV. This gave dl-lla-ethyl-8a-oestradiol with 17% yield, melting point llO-114 C.
Example VIII
dl-lla-Ethyl-17-methyl-8a-oestra-1,3~ 0),13(17)-tetraene-l-ol (formula (1): Rl = H, R2 = OH, R3 = ethyl, R4 = H(~OH)) A mixture of 2.0 9 (7.6 mmol) triphenyl phosphine, 35 1.06 9 (0.152 mol) lithium and 100 ml dry tetrahydro-~ ~ 7~
furan was stirred under nitrogen at room temperature until the lithium had dissolved ~about 2 hours).
Then 3.0 g (10 mmol) of l-methoxy-isomer from example Vd) and 7.5 ml tetramethyl ethylene diamine was added. The mixture obtained was boiled for
and then poured into cold water. The organic layer was separated off, washed with water and dried on anhydrous magnesium sulphate. The solvent was evaporated off under reduced pressure and the residue was sub~ected to chromatography over 300 9 silicagel with hexane/ethyl acetate 95:5. Initially 2.3 g dl-2,2-diethyl-4-(5-methyl-2-furyl)-butane nitrile was eluated, followed by 9.5 9 (58% yield) dl-2-ethyl-4-(5-methyl-2-furyl)-butane nitrile.
b~ dl-2-Ethy_-4-(5-methY1-2-furyl)-butanal (formula (3): R3 = ethyl, R7 = methyl, Z = 0~
The product from example Va) was reduced in a manner analogous to that described in example Ib) to the corresponding aldehyde, with 49% yield.
c) dl-2-r(Z)-6-(3-methoxvphenyl)-2-ethyl-hexenyll-3-meth~1-2-c~cloPentenone ~formula (6), R3 ~ C2H5, R7 = CH3, R5 = methoxy, R6 = H) The product from example Ib) was subjected to a Wittig reaction as de~cribed in example Ic) and then converted to the cyclopentenone derivative mentioned in the preamble, in a manner similar to that described in example Id). These reactions gave an overall yield of 62%.
i ~ 7 ~
d) dl-l- and dl-3-methoxy-lla-ethyl-17-methyl-8~-qona-1,3,5(10),13(17)-tetraene (formula (8), R3 = C2H5, Rl = H, R2 = methoxy or Rl = methoxy, R2 = H) S The cyclopentenone from example Vd) was reduced and cyclized in a manner analogous to that described in example Ie). The l-methoxy isomer was isolated, with 12% yield, melting point 107-108 C
(recrystallisation from methanol) and the 3-methoxy isomer with 43.6% yield, melting point 89-90 C
(from methanol).
Example VI
dl-lla-EthYl-8a-oestrone methYl ether (formula (10), Rl = methoxy, R2 ~ H~ R3 = C2H5) The 3-methoxy isomer from example Vd) was oxidised and reacted in a manner analogous to that described in example II. In this way dl-lla-ethyl-8a-oestrone methyl ether was obtained with 25% yield (oil).
Example VII
dl-lla-Ethyl-8a-oestradiol (formula (1): Rl = OH, R2 = H, R3 = ethyl, R4 = H(~OH)) The oestrone derivative from example VI was reduced and demethylated in the manner as described in examples III and IV. This gave dl-lla-ethyl-8a-oestradiol with 17% yield, melting point llO-114 C.
Example VIII
dl-lla-Ethyl-17-methyl-8a-oestra-1,3~ 0),13(17)-tetraene-l-ol (formula (1): Rl = H, R2 = OH, R3 = ethyl, R4 = H(~OH)) A mixture of 2.0 9 (7.6 mmol) triphenyl phosphine, 35 1.06 9 (0.152 mol) lithium and 100 ml dry tetrahydro-~ ~ 7~
furan was stirred under nitrogen at room temperature until the lithium had dissolved ~about 2 hours).
Then 3.0 g (10 mmol) of l-methoxy-isomer from example Vd) and 7.5 ml tetramethyl ethylene diamine was added. The mixture obtained was boiled for
5 hours under reflux cooling, after which water was added and extracted with ethyl acetate. The extracts were washed with saturated common salt solution, dried on anhydrous sodium sulphate and concentrated.
The residue was sub~ected to chromato~raphy over 100 g silicagel with hexane/ethyl acetate 95:5.
3.0 9 Of the product mentioned in the preamble was obtained. Recrystallisation from hexane gave a pure specimen with a melting point of 140-142 C.
Example IX
dl-lla-EthYl-l-hydroxY-8-oestra-1,3,5(10)-triene-17-one benzoate (formula (1): Rl = H, R2 = benzoyloxy, R3 = ethyl, R4 ~ 0) The product from example VIII (3.0 ~) was dissolved in 100 ml dry pyridine and treated at 0 C
with 7.0 g (5 equiv.) benzoyl chloride. After 2 hours at 0 C the reaction mixture was poured into water and extracted with ether. The extracts were washed successively with 2 N hydrochloric acid, water and saturated sodium bicarbonate solution and dried on anhydrous sodium sulphate. The product obtained after concentration was epoxidised in the same way as described in example IIa) and then treated with borotrifluoride etherate and processed as described in example IIb). This gave 665 mg (16~ yield~ of pure 17-ketone-1-benzoate.
~ ~ 7 ~ 5 ~
Example X
dl-lla-Ethyl-8a-oestra-1,3,5(10)-triene-1,17~-diol The 17-ketone-1-benzoate from example IX was treated with lithium aluminium anhydride in a similar manner to that described in example III.
The pure 1,17~-diol, after crystallisation from chloroform/hexane, was obtained with 68% yield, melting point 155-157 C.
Example XI
dl-l-Hydroxy-lla-methvl-8a-oestra-1,3,5(10)-triene-17-one benzoate (formula (1), Rl = H, R2 = benzoyloxy, R3 = methyl, R4 ~ O) The l-methoxy isomer from example Ie) was reacted in a manner analogous to that described in examples VIII and IX to the benzoate mentioned in the preamble, giving 18X overall yield, melting point 138-139 C.
Example XII
dl-lla-MethYl-8a-oestra-1.3,5(10)-triene-1,17~-diol (formula (1), Rl = H, R2 = OH, R3 = methyl, R4 = H~OH)) The 17-ketone-1-benzoate from example XI was treated with lithium aluminium hydride In a manner analogous to that described in example III. After crystallisation from ether the pure diol was obtained with 72% yield, melting point 212-213 C.
Example XIII
dl-3-Hvdroxy-lla-methvl-8a-oestra-1.3,5(10)-triene-17-one-benzoate (formula (1), Rl ~ benzoyloxy, R2 = H~ R3 = methyl, R4 = o) The 3-methoxy-isomer from example Ie) was reacted in a manner analogous to that described in examples VIII and IX to the 17-ketone-3-benzoate, melting point 206-207 C, 16% overall yield.
Example XIV
dl-17a-EthYnyl-lla-methvl-8a-oestra-1,3,5(10)-triene-3,17~diol (formula (1): Rl = OH, R2 = H, R3 = methyl, R4 = (a-ethynyl)(~OH)) Acetylene was passed for 2 hours through a suspension of 1.7 g (15 mmol) potassium-t-butylate in 30 ml dry tetrahydrofuran which had been cooled to O C. The 17-ketone from example XIII (0.40 g, 1 mmol) dissolved in 20 ml dry tetrahydrofuran was added dropwise during stirring. Stirring was continued for 5 hours at O-S C whilst still passing acetylene through. The reaction mixture was mixed with water and extracted with ethyl acetate. The extracts were washed with water, dried on anhydrous magnesium sulphate and concentrated. The crude product was sub~ected to chromatography above 50 g sillcagel with hexane/ethyl acetate 7:3 and recrystallised out of ethyl acetate/hexane. This gave 0.273 g 17a-ethynyl product (88% yield), melting point 186-187 C.
Example XV
lla-Meth~1-8a-oestradiol methyl ether (formula ~1):
Rl = methoxy, R2 = H, R3 = methyl, R4 = H~OH~) a) The dl product from example III (1.5 g, 5 mmol) was dissolved in 10 ml pyridine. Phthallc acid anhydride (3.0 g, 20 m~ol) was added and the mixture was boiled under nitrogen for 2~ hours under reflux cooling. The reaction mixture was cooled, poured into 250 ml of 2 N hydrochloric acid and stirred for 3 hours at room temperature. The resultant deposit was sucked off, washed with warm water, dried and ~ ~ ~ 36~
recrystallised out of dichloromethane/methanol.
2.15 g Hemiphthalate (96% yield) was obtained, melting point 225-226 C.
b) The hemiphthalate obtained in example XVa) S (2.15 g, 4.8 mmol) was suspended in 60 ml methanol, after which 1.41 g (4.8 mmol) cinchonine was added.
The mixture was brouqht to the boil and then cooled slowly to 0 C. After standing for 4 hours at 0 C
the resultant deposit was sucked off (0.92 g). The filtrate was concentrated to a volume of 16 ml and, after adding an inoculation crystal, was stored for 16 hours at 0 C. The resultant deposit was sucked off (0.62 g). The flltrate was concentrated and once again was recrystallised in the same manner out of 10 ml methanol. Prom this 0.18 g of crystals were obtained, so that in total 1.72 g crystalline material was obtained.
c) The crystalline cinchonine salt (1.72 g, 2.3 mmolj obtained in example XVb) was suspended in 17 ml methanol and treated at 0 C with 35 ml 3 N sulphuric acid. The mixture was stirred for 3 hours at 0 C. The resultant deposit was sucked off, washed with water until neutral, dried and recrystallised out of dichloromethane/methanol.
0.99 g d-hemiphthalate (95.5% yield) was obtained, melting point 225 C, []20 = +42.3 (CHC13).
d) The d-hemiphthalate (0.99 g, 2.2 mmol) obtained in example XVd) was dissolved in 22 ml methanol.
Potassium hydroxide (1.30 g, 23 mmol) wa~ added and the mixture obtained was boiled for S hours under reflux cooling. The reaction mixture was cooled, mixed with water and extracted with dichloromethane.
The extracts were washed until neutral with water, dried on anhydrous sodium sulphate and concentrated.
The residue was recrystallised from 5 ml of ether.
~ 7 ', 3S~ ~ `
This gave 0.19 9 crystals of optical impure compound, melting point 129-133 C, [a]D = +9.5 (CHC13) and on evaporation of the mother-lye 0.41 9 of optical pure lla-methyl-8a-oestradiol methyl ether, melting point 122-125 C, [a]D = ~19.5 (CHC13) was obtained.
Example XVI
ent-lla-Methyl-8a-oestradiol methvl ether (formula (1): Rl = methoxy, R2 = H, R3 = methyl, R4 = H(~OH)) Evaporation of the mother liquor obtained in example XVb~ gave 1.86 9 of low-melting point cinchonine salt. Decomposition with 3 N sulphuric acid as described in example XVc) gave 0.94 g of l-hemiphthalate (84% yield), melting point 225 C, [a]D = -40.8 (CHC13).
Saponification of this, as described in example XVd), supplied 0.49 g (76% yield) ent-ll-methyl-8a-oestradiol methyl ether, melting point 122-126 C, [a~D = -17.7 (CHC13) and 0.18 g of optical less pure compound having a melting point of 129-132 C and [alD of -10.0 (CHC13).
Example XVII
11-Methyl-8a-oestradiol (formula (1): R = OH, R2 H, R3 = methyl, R4 = H(~OH)) The methyl ether from example XVd) was demethylated in a manner similar to that described in example VIII. The crude product was purified by chromatography above silicagel with hexane/acetonè
8:2. The lla-methyl-8a-oestradiol was isolated in quantitative yield, melting point 183-185 C, [a]D = ~26.1 ttetrahydrofuran).
The residue was sub~ected to chromato~raphy over 100 g silicagel with hexane/ethyl acetate 95:5.
3.0 9 Of the product mentioned in the preamble was obtained. Recrystallisation from hexane gave a pure specimen with a melting point of 140-142 C.
Example IX
dl-lla-EthYl-l-hydroxY-8-oestra-1,3,5(10)-triene-17-one benzoate (formula (1): Rl = H, R2 = benzoyloxy, R3 = ethyl, R4 ~ 0) The product from example VIII (3.0 ~) was dissolved in 100 ml dry pyridine and treated at 0 C
with 7.0 g (5 equiv.) benzoyl chloride. After 2 hours at 0 C the reaction mixture was poured into water and extracted with ether. The extracts were washed successively with 2 N hydrochloric acid, water and saturated sodium bicarbonate solution and dried on anhydrous sodium sulphate. The product obtained after concentration was epoxidised in the same way as described in example IIa) and then treated with borotrifluoride etherate and processed as described in example IIb). This gave 665 mg (16~ yield~ of pure 17-ketone-1-benzoate.
~ ~ 7 ~ 5 ~
Example X
dl-lla-Ethyl-8a-oestra-1,3,5(10)-triene-1,17~-diol The 17-ketone-1-benzoate from example IX was treated with lithium aluminium anhydride in a similar manner to that described in example III.
The pure 1,17~-diol, after crystallisation from chloroform/hexane, was obtained with 68% yield, melting point 155-157 C.
Example XI
dl-l-Hydroxy-lla-methvl-8a-oestra-1,3,5(10)-triene-17-one benzoate (formula (1), Rl = H, R2 = benzoyloxy, R3 = methyl, R4 ~ O) The l-methoxy isomer from example Ie) was reacted in a manner analogous to that described in examples VIII and IX to the benzoate mentioned in the preamble, giving 18X overall yield, melting point 138-139 C.
Example XII
dl-lla-MethYl-8a-oestra-1.3,5(10)-triene-1,17~-diol (formula (1), Rl = H, R2 = OH, R3 = methyl, R4 = H~OH)) The 17-ketone-1-benzoate from example XI was treated with lithium aluminium hydride In a manner analogous to that described in example III. After crystallisation from ether the pure diol was obtained with 72% yield, melting point 212-213 C.
Example XIII
dl-3-Hvdroxy-lla-methvl-8a-oestra-1.3,5(10)-triene-17-one-benzoate (formula (1), Rl ~ benzoyloxy, R2 = H~ R3 = methyl, R4 = o) The 3-methoxy-isomer from example Ie) was reacted in a manner analogous to that described in examples VIII and IX to the 17-ketone-3-benzoate, melting point 206-207 C, 16% overall yield.
Example XIV
dl-17a-EthYnyl-lla-methvl-8a-oestra-1,3,5(10)-triene-3,17~diol (formula (1): Rl = OH, R2 = H, R3 = methyl, R4 = (a-ethynyl)(~OH)) Acetylene was passed for 2 hours through a suspension of 1.7 g (15 mmol) potassium-t-butylate in 30 ml dry tetrahydrofuran which had been cooled to O C. The 17-ketone from example XIII (0.40 g, 1 mmol) dissolved in 20 ml dry tetrahydrofuran was added dropwise during stirring. Stirring was continued for 5 hours at O-S C whilst still passing acetylene through. The reaction mixture was mixed with water and extracted with ethyl acetate. The extracts were washed with water, dried on anhydrous magnesium sulphate and concentrated. The crude product was sub~ected to chromatography above 50 g sillcagel with hexane/ethyl acetate 7:3 and recrystallised out of ethyl acetate/hexane. This gave 0.273 g 17a-ethynyl product (88% yield), melting point 186-187 C.
Example XV
lla-Meth~1-8a-oestradiol methyl ether (formula ~1):
Rl = methoxy, R2 = H, R3 = methyl, R4 = H~OH~) a) The dl product from example III (1.5 g, 5 mmol) was dissolved in 10 ml pyridine. Phthallc acid anhydride (3.0 g, 20 m~ol) was added and the mixture was boiled under nitrogen for 2~ hours under reflux cooling. The reaction mixture was cooled, poured into 250 ml of 2 N hydrochloric acid and stirred for 3 hours at room temperature. The resultant deposit was sucked off, washed with warm water, dried and ~ ~ ~ 36~
recrystallised out of dichloromethane/methanol.
2.15 g Hemiphthalate (96% yield) was obtained, melting point 225-226 C.
b) The hemiphthalate obtained in example XVa) S (2.15 g, 4.8 mmol) was suspended in 60 ml methanol, after which 1.41 g (4.8 mmol) cinchonine was added.
The mixture was brouqht to the boil and then cooled slowly to 0 C. After standing for 4 hours at 0 C
the resultant deposit was sucked off (0.92 g). The filtrate was concentrated to a volume of 16 ml and, after adding an inoculation crystal, was stored for 16 hours at 0 C. The resultant deposit was sucked off (0.62 g). The flltrate was concentrated and once again was recrystallised in the same manner out of 10 ml methanol. Prom this 0.18 g of crystals were obtained, so that in total 1.72 g crystalline material was obtained.
c) The crystalline cinchonine salt (1.72 g, 2.3 mmolj obtained in example XVb) was suspended in 17 ml methanol and treated at 0 C with 35 ml 3 N sulphuric acid. The mixture was stirred for 3 hours at 0 C. The resultant deposit was sucked off, washed with water until neutral, dried and recrystallised out of dichloromethane/methanol.
0.99 g d-hemiphthalate (95.5% yield) was obtained, melting point 225 C, []20 = +42.3 (CHC13).
d) The d-hemiphthalate (0.99 g, 2.2 mmol) obtained in example XVd) was dissolved in 22 ml methanol.
Potassium hydroxide (1.30 g, 23 mmol) wa~ added and the mixture obtained was boiled for S hours under reflux cooling. The reaction mixture was cooled, mixed with water and extracted with dichloromethane.
The extracts were washed until neutral with water, dried on anhydrous sodium sulphate and concentrated.
The residue was recrystallised from 5 ml of ether.
~ 7 ', 3S~ ~ `
This gave 0.19 9 crystals of optical impure compound, melting point 129-133 C, [a]D = +9.5 (CHC13) and on evaporation of the mother-lye 0.41 9 of optical pure lla-methyl-8a-oestradiol methyl ether, melting point 122-125 C, [a]D = ~19.5 (CHC13) was obtained.
Example XVI
ent-lla-Methyl-8a-oestradiol methvl ether (formula (1): Rl = methoxy, R2 = H, R3 = methyl, R4 = H(~OH)) Evaporation of the mother liquor obtained in example XVb~ gave 1.86 9 of low-melting point cinchonine salt. Decomposition with 3 N sulphuric acid as described in example XVc) gave 0.94 g of l-hemiphthalate (84% yield), melting point 225 C, [a]D = -40.8 (CHC13).
Saponification of this, as described in example XVd), supplied 0.49 g (76% yield) ent-ll-methyl-8a-oestradiol methyl ether, melting point 122-126 C, [a~D = -17.7 (CHC13) and 0.18 g of optical less pure compound having a melting point of 129-132 C and [alD of -10.0 (CHC13).
Example XVII
11-Methyl-8a-oestradiol (formula (1): R = OH, R2 H, R3 = methyl, R4 = H(~OH)) The methyl ether from example XVd) was demethylated in a manner similar to that described in example VIII. The crude product was purified by chromatography above silicagel with hexane/acetonè
8:2. The lla-methyl-8a-oestradiol was isolated in quantitative yield, melting point 183-185 C, [a]D = ~26.1 ttetrahydrofuran).
6 ~ ~
Example XVIII
ent-lla-Methyl-8a-oestradiol (formula (1): Rl = OH, R2 = H, R3 = methyl, R4 = H(~OH)) This enantiomer was obtained from the enantiomer from example XVI in a manner analogous to that described in examples VIII and XVII.
Melting point 182-184 C, [alD = -23.4 (tetra-hydrofuran).
Example XIX
a) 3-(3,5-dimethoxyphenvl)-proPYltriphenyl phosphonium bromide (formula (2): R5 = R6 =
methoxy; A = P(phenyl)3) A mixture of 25.8 g (0.10 mol) 1-(3-bromopropyl)-3,5-dimethoxy benzene, 32.0 g (0.12 mol) triphenyl-phosphine and 50 ml toluene was heated for 16 hours at 110 C. The reaction mixture was cooled down and the resultant deposit was filtered off. The crystals were washed with toluene and dried. Yield 50.7 g of phosphonium bromide (97%), melting point 171-172 C.
b) dl-(Z)-1-~3,5-dimethoxvphenyl)-5-methYl-7-(5-methyl-2-furYl)-3-heptene (formula (4):
3 R7 CH3, R5 = R6 = methoxy) Wittig condensation of the phosphonium salt obtained in example XIXa) with the aldehyde from example Ib) in the manner described in example Ic) gave, with 82X yield, the (Z)-isomer mentioned in the preamble mixed with approximately 10% (E) isomer.
c) dl-(Z)-2-r6-(3,5-dimethoxYPhenyl)-2-methYl-3-hexenY11-3-methYl-2_cvclopentenone (formula (6):
R3 = R7 = CH3~ Rs = R6 = methoxy) The Wittig product from example XIXb) was reacted in a manner analogous to that described in example Id) to give the desired cyclopentenone. From the mixture originally obtained of 90% (Z~- and 10% (E)-isomer, ~ ~ i7 ~
the pure (z) isomer was isolated with 72% yield.
d) dl-1,3-Dimethoxy-11,17-dimethyl-8a-qona-1,3,5(10),13(17)-tetraene (formula (8): Rl - R2 =
methoxy, R3 = CH3) S The Z-isomer from example XIXc) was reduced and cyclized in a manner analogous to that described in example Ie). The pure gonatetraene derivative was obtained by crystallisation from methanol with 64~ yield, melting point 81-82 C.
Example XX
dl-l-Methoxy-lla,17-dimethyl-8-qona-1,3,5(10)l13(17)-tetraene-3-ol (formula (8): Rl = OH, R2 = methoxy, R3 = CH3) Treatment of the gonatetraene derivative from example XIXc) with lithium diphenyl phosphide in a manner as described in example VIII gave the l-methoxy-3-ol-derivative in 35% yield, melting point 150-153 C
Example XXI
dl-1,3-dimethoxy-11-methyl-8a-oestra-1,3,5(10)-triene-17-one (formula (10): Rl = R2 = methoxy, R3 = methyl) The gonatetraene derivative from example XIXc) was epoxidized as described in example IIa) and then treated with borotrifluoride etherate as described in example IIb). From thls the desired 17-ketone was obtained with 17% yield.
Example XXII
Dimethoxy-lla-methyl-8a-oestra-1,3,5(10~-triene-17~-ol (formula (1): Rl = R = methoxy, R3 = methyl, R4 = H(~OH)) The 17-ketone from example XXI was reduced as t i ~ i 5 t described in example III to the oestradiol derivative, with 80% yield, melting point 91-99 C.
Example XXIII
dl-lla-Methvl-8a-oestra-1,3,5(10)-triene-1,3,17-triol (formula (1): Rl = R2 = OH, R3 = methyl, R4 = H(~OH)) The oestradiol derivative from example XXII
(0.66 g, 2 mmol) was mixed with 35 ml dichloro-methane and 0.66 ml boron tribromide and was heated for 30 minutes at 30 C~ The reaction mixture was washed with sodium bicarbonate solution, dried on anhydrous Na2S04 and concentrated. The residue was subjected to chromatography above silicagel with hexane/ethyl acetate 1:1 and the product was crystallised out of ether. Yield 0.43 g (80%) 1~3,17-triol, melting point 262-264 C.
~ xample XXIV
dl-ll-Methyl-8a-oestra-1,3,5(10)-triene-1,3,17~-triol triacetate (formula (1): Rl = R2 = acetoxy,R3 = methyl, R4 = H(~-acetoxy)).
The triol from example XXIII (0.1 g) was acetylated in pyridine (S ml) with acetic acid anhydride (2 ml). After stirring for 1 hour at 75 C the reaction mixture was diluted by carefully adding water. Processing in the normal manner gave, in fairly quantitative yield, dl-lla-methyl-8a-oestra-1,3,5(10)-triene-i,3,17~-triol triacetate.
Example XVIII
ent-lla-Methyl-8a-oestradiol (formula (1): Rl = OH, R2 = H, R3 = methyl, R4 = H(~OH)) This enantiomer was obtained from the enantiomer from example XVI in a manner analogous to that described in examples VIII and XVII.
Melting point 182-184 C, [alD = -23.4 (tetra-hydrofuran).
Example XIX
a) 3-(3,5-dimethoxyphenvl)-proPYltriphenyl phosphonium bromide (formula (2): R5 = R6 =
methoxy; A = P(phenyl)3) A mixture of 25.8 g (0.10 mol) 1-(3-bromopropyl)-3,5-dimethoxy benzene, 32.0 g (0.12 mol) triphenyl-phosphine and 50 ml toluene was heated for 16 hours at 110 C. The reaction mixture was cooled down and the resultant deposit was filtered off. The crystals were washed with toluene and dried. Yield 50.7 g of phosphonium bromide (97%), melting point 171-172 C.
b) dl-(Z)-1-~3,5-dimethoxvphenyl)-5-methYl-7-(5-methyl-2-furYl)-3-heptene (formula (4):
3 R7 CH3, R5 = R6 = methoxy) Wittig condensation of the phosphonium salt obtained in example XIXa) with the aldehyde from example Ib) in the manner described in example Ic) gave, with 82X yield, the (Z)-isomer mentioned in the preamble mixed with approximately 10% (E) isomer.
c) dl-(Z)-2-r6-(3,5-dimethoxYPhenyl)-2-methYl-3-hexenY11-3-methYl-2_cvclopentenone (formula (6):
R3 = R7 = CH3~ Rs = R6 = methoxy) The Wittig product from example XIXb) was reacted in a manner analogous to that described in example Id) to give the desired cyclopentenone. From the mixture originally obtained of 90% (Z~- and 10% (E)-isomer, ~ ~ i7 ~
the pure (z) isomer was isolated with 72% yield.
d) dl-1,3-Dimethoxy-11,17-dimethyl-8a-qona-1,3,5(10),13(17)-tetraene (formula (8): Rl - R2 =
methoxy, R3 = CH3) S The Z-isomer from example XIXc) was reduced and cyclized in a manner analogous to that described in example Ie). The pure gonatetraene derivative was obtained by crystallisation from methanol with 64~ yield, melting point 81-82 C.
Example XX
dl-l-Methoxy-lla,17-dimethyl-8-qona-1,3,5(10)l13(17)-tetraene-3-ol (formula (8): Rl = OH, R2 = methoxy, R3 = CH3) Treatment of the gonatetraene derivative from example XIXc) with lithium diphenyl phosphide in a manner as described in example VIII gave the l-methoxy-3-ol-derivative in 35% yield, melting point 150-153 C
Example XXI
dl-1,3-dimethoxy-11-methyl-8a-oestra-1,3,5(10)-triene-17-one (formula (10): Rl = R2 = methoxy, R3 = methyl) The gonatetraene derivative from example XIXc) was epoxidized as described in example IIa) and then treated with borotrifluoride etherate as described in example IIb). From thls the desired 17-ketone was obtained with 17% yield.
Example XXII
Dimethoxy-lla-methyl-8a-oestra-1,3,5(10~-triene-17~-ol (formula (1): Rl = R = methoxy, R3 = methyl, R4 = H(~OH)) The 17-ketone from example XXI was reduced as t i ~ i 5 t described in example III to the oestradiol derivative, with 80% yield, melting point 91-99 C.
Example XXIII
dl-lla-Methvl-8a-oestra-1,3,5(10)-triene-1,3,17-triol (formula (1): Rl = R2 = OH, R3 = methyl, R4 = H(~OH)) The oestradiol derivative from example XXII
(0.66 g, 2 mmol) was mixed with 35 ml dichloro-methane and 0.66 ml boron tribromide and was heated for 30 minutes at 30 C~ The reaction mixture was washed with sodium bicarbonate solution, dried on anhydrous Na2S04 and concentrated. The residue was subjected to chromatography above silicagel with hexane/ethyl acetate 1:1 and the product was crystallised out of ether. Yield 0.43 g (80%) 1~3,17-triol, melting point 262-264 C.
~ xample XXIV
dl-ll-Methyl-8a-oestra-1,3,5(10)-triene-1,3,17~-triol triacetate (formula (1): Rl = R2 = acetoxy,R3 = methyl, R4 = H(~-acetoxy)).
The triol from example XXIII (0.1 g) was acetylated in pyridine (S ml) with acetic acid anhydride (2 ml). After stirring for 1 hour at 75 C the reaction mixture was diluted by carefully adding water. Processing in the normal manner gave, in fairly quantitative yield, dl-lla-methyl-8a-oestra-1,3,5(10)-triene-i,3,17~-triol triacetate.
Claims (37)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of novel 8.alpha.-oestra-1,3,5(10) -triene derivatives substituted at the 11.alpha.-position by an alkyl group with 1-4 carbon atoms and having the formula (1):
(1) wherein R1 stands for H or a free, esterified or etherified hydroxy group;
R2 stands for H or a free, esterified or etherified hydroxy group, with the proviso that at least one of the substituents R1 and R2 is different from H;
R3 stands for alkyl (1-4 C) and R4 stands for O or (.alpha.X)(.beta.Y), wherein X stands for H or aliphatic hydrocarbyl (1-4 C) and Y stands for a free, esterified or etherified hydroxy group;
and the enantiomers and racemic mixtures thereof, characterized by treating a 13.alpha.,17.alpha.-epoxy steroid of the formula (9) (9) wherein R1, R2 and R3 have the meanings given hereinbefore, with an acid to give a compound having the formula (1), wherein R4 stands for O, and, if required, the compound obtained is alkylated or reduced in 17-position, any hydroxy group present is esterified or etherified and/or any ester group or ether group is hydrolyzed, and/
or any racemate is resolved.
(1) wherein R1 stands for H or a free, esterified or etherified hydroxy group;
R2 stands for H or a free, esterified or etherified hydroxy group, with the proviso that at least one of the substituents R1 and R2 is different from H;
R3 stands for alkyl (1-4 C) and R4 stands for O or (.alpha.X)(.beta.Y), wherein X stands for H or aliphatic hydrocarbyl (1-4 C) and Y stands for a free, esterified or etherified hydroxy group;
and the enantiomers and racemic mixtures thereof, characterized by treating a 13.alpha.,17.alpha.-epoxy steroid of the formula (9) (9) wherein R1, R2 and R3 have the meanings given hereinbefore, with an acid to give a compound having the formula (1), wherein R4 stands for O, and, if required, the compound obtained is alkylated or reduced in 17-position, any hydroxy group present is esterified or etherified and/or any ester group or ether group is hydrolyzed, and/
or any racemate is resolved.
2. A process as claimed in claim 1, characterized in that the acid is an aprotic Lewis acid.
3. A process as claimed in claim 2, characterized in that the aprotic Lewis acid is borontrifluoride-etherate.
4. A process as claimed in claim 1, characterized in that the reaction is carried out in a solvent at a temperature between -100°C and +80°C.
5. A process as claimed in claim 4, characterized in that the solvent is toluene.
6. A process as claimed in claim 1, characterized in that the 13.alpha.,17.alpha.-epoxy steroid of formula (9) has been prepared by cyclizina a (Z)-olefinic polyene of the formula (7) (7) wherein R3 stands for alkyl (1-4 C); R5 and/or R6 stands for hydroxy, hydrocarbyloxy (1-8 C), trimethylsilyloxy, tetrahydropyran-yloxy or carboxyacyloxy (1-7 C);R7 stands for H or CH3 and R8 stands for H or CH3 with the proviso, that R8 stands for H when R7 stands for CH3 and R8 stands for CH3 when R7 stands for H;
under acid conditions with the aid of a Lewis acid to give an alkyl-8.alpha.-steroid of the formula (8) (8) wherein R1, R2 and R3 have the meanings as given hereinbefore, whereafter the double bond in 13,17-position is epoxidized with a peroxy acid.
under acid conditions with the aid of a Lewis acid to give an alkyl-8.alpha.-steroid of the formula (8) (8) wherein R1, R2 and R3 have the meanings as given hereinbefore, whereafter the double bond in 13,17-position is epoxidized with a peroxy acid.
7. A compound of the general formula (1), as defined in claim 1, wherever prepared by the process of claim 1, or by an obvious chemical equivalent thereof.
8. A process as claimed in claim 1, characterized in that R1 stands for H, hydroxy, hydrocarbyloxy (1-8 C), trimethylsilyloxy, tetrahydropyranyloxy or carboxyacyloxy (1-7 C);
R2 stands for H or is equal to R1; with the proviso that at least one of the substituents R1 and R2 is not equal to H;
R3 stands for methyl or ethyl; and R4 stands for O, (.alpha.X)(.beta.OH) or (.alpha.X)(.beta.Oacetyl).
R2 stands for H or is equal to R1; with the proviso that at least one of the substituents R1 and R2 is not equal to H;
R3 stands for methyl or ethyl; and R4 stands for O, (.alpha.X)(.beta.OH) or (.alpha.X)(.beta.Oacetyl).
9. A compound of the formula (1) wherein R1, R2, R3 and R4 are as defined in claim 8, whenever prepared by the process of claim 8, or by an obvious chemical equivalent thereof.
10. A process as claimed in claim 8, characterized in that R4 stands for O (.alpha.H)(.beta.OH) or (.alpha.-ethynyl)(.beta.OH).
11. A compound of the formula (1) wherein R1, R2 and R3 are as defined in claim 8 and R4 is as defined in claim 10, whenever prepared by the process of claim 10, or by an obvious chemical equivalent thereof.
12. A process as claimed in claim 8, characterized in that R1 is H, OH, methoxy or benzoyloxy and R2 is H, OH, methoxy or benzoyloxy, whereby at least one of the substituents R1 and R2 is not equal to H.
13. A compound of the formula (1) wherein R1 and R2 are as defined in claim 12, and R3 and R4 are as defined in claim 8, wherever prepared by the process of claim 12 or by an obvious chemical equivalent thereof.
14. A process as claimed in claim 10, characterized in that R1 is H, OH, methoxy or benzoyloxy and R2 is H, OH, methoxy or benzoyloxy, whereby at least one of the substituents R1 and R2 is not equal to H.
15. A compound of the formula (1) wherein R1 and R2 are as defined in claim 14, R4 is as defined in claim 10, and R3 is as defined in claim 8, whenever prepared by the process of claim 14 or by an obvious chemical equivalent thereof.
16. A process for preparing dl-11.alpha.-methyl-8.alpha.-oestrone methyl ether, which process comprises treating dl-3-methoxy-11.alpha.-,17-dimethyl-13.alpha.,17.alpha.-epoxy-8.alpha.-gona-1,3,5(10)-triene with an aprotic Lewis acid.
17. dl-11.alpha.-Methyl-8.alpha.-oestrone methyl ether, whenever prepared or produced by the process of claim 16 or by an obvious chemical equivalent.
18. A process for preparing dl-11.alpha.-methyl-8.alpha.-oestradiol or an ester thereof with 1 to 18 C atoms in the acyl moiety, which process comprises:
reducing the 17-position keto group in dl-11.alpha.-methyl-8.alpha.-oestrone methyl ether prepared according to claim 16 to a hydroxy group whereby obtaining dl-11.alpha.-methyl-8.alpha.-oestradiol 3-methyl ether, hydrolytically removing the 3-methyl group to obtain dl-11.alpha.-methyl-8.alpha.-oestradiol, and if required esterifying at least one hydroxy group in the diol to obtain an ester thereof.
reducing the 17-position keto group in dl-11.alpha.-methyl-8.alpha.-oestrone methyl ether prepared according to claim 16 to a hydroxy group whereby obtaining dl-11.alpha.-methyl-8.alpha.-oestradiol 3-methyl ether, hydrolytically removing the 3-methyl group to obtain dl-11.alpha.-methyl-8.alpha.-oestradiol, and if required esterifying at least one hydroxy group in the diol to obtain an ester thereof.
19. dl-11.alpha.-Methyl-8.alpha.-oestradiol or an ester thereof with 1 to 18 C atoms in the acyl moiety, whenever prepared or produced by thé process of claim 18 or by an obvious chemical equivalent thereof.
20. A process for producing 11.alpha.-methyl-8.alpha.-oestradiol, methyl ether thereof, an ester of the methyl ether thereof with 1 to 18 C
atoms in the acyl moiety, or an ester of the diol with 1 to 18 C
atoms, in the acyl moiety, which process comprises:
reducing the 17-position keto group in dl-11.alpha.-methyl-8.alpha.-oestrone methyl ether prepared according to claim 16 to a hydroxy group whereby obtaining dl-11.alpha.-methyl-8.alpha.-oestradiol methyl ether;
resolving the dl methyl ether into optical isomers to obtain 11.alpha.-methyl-8.alpha.-oestradiol methyl ether with positive optical polarity, if required esterifying the thus prepared diol monoether to obtain an ester thereof with 1 to 18 C atoms in the acyl moiety, if required hydrolytically removing the 3-methyl group of the thus prepared 11.alpha.-methyl-8.alpha.-oestradiol, methyl ether to obtain 11.alpha.-methyl-8.alpha.-oestradiol, if required, esterifying at least one hydroxy group of the thus prepared 11.alpha.-methyl-8.alpha.-oestradiol to obtain an ester of 11.alpha.-methyl-8.alpha.-oestradiol with 1 to 18 C atoms in the acyl moiety.
atoms in the acyl moiety, or an ester of the diol with 1 to 18 C
atoms, in the acyl moiety, which process comprises:
reducing the 17-position keto group in dl-11.alpha.-methyl-8.alpha.-oestrone methyl ether prepared according to claim 16 to a hydroxy group whereby obtaining dl-11.alpha.-methyl-8.alpha.-oestradiol methyl ether;
resolving the dl methyl ether into optical isomers to obtain 11.alpha.-methyl-8.alpha.-oestradiol methyl ether with positive optical polarity, if required esterifying the thus prepared diol monoether to obtain an ester thereof with 1 to 18 C atoms in the acyl moiety, if required hydrolytically removing the 3-methyl group of the thus prepared 11.alpha.-methyl-8.alpha.-oestradiol, methyl ether to obtain 11.alpha.-methyl-8.alpha.-oestradiol, if required, esterifying at least one hydroxy group of the thus prepared 11.alpha.-methyl-8.alpha.-oestradiol to obtain an ester of 11.alpha.-methyl-8.alpha.-oestradiol with 1 to 18 C atoms in the acyl moiety.
21. 11.alpha.-Methyl-8.alpha.-oestradiol methyl ether thereof, an ester of the methyl ether thereof with 1 to 18 C atoms in the acyl moiety, or an ester of the diol with 1 to 18 C atoms in the acyl moiety, whenever prepared or produced by the process of claim 20 or by an obvious chemical equivalent thereof.
22. A process for producing ent-11.alpha.-methyl-8.alpha.-oestradiol, methyl ether thereof, an ester of the methyl ether thereof with 1 to 18 C atoms in the acyl moiety or an ester of the diol with 1 to 18 C atoms in the acyl moiety, which process comprises:
reducing the 17-position keto group in dl-11.alpha.-methyl-8.alpha.-oestrone methyl ether prepared according to claim 16 to a hydroxy group whereby obtaining dl-11.alpha.-methyl-8.alpha.-oestradiol methyl ether, resolving the dl methyl ether into optical isomers to obtain ent-11.alpha.-methyl-8.alpha.-oestradiol methyl ether with negative optical polarity, if required esterifying the thus prepared diol monoether to obtain an ester thereof with 1 to 18 C atoms in the acyl moiety, if required hydrolytically removing the 3-methyl group of the thus prepared ent-11.alpha.-methy1-8.alpha.-oestradiol methyl ether to obtain ent-11.alpha.-methyl-8.alpha.-oestradiol, if required esterifying at least one hydroxy group of the thus prepared ent11.alpha.--methyl-8.alpha.-oestradiol to obtain an ester of ent-11.alpha.-methyl-8.alpha.-oestradiol with 1 to 18 C atoms in the acyl moiety.
reducing the 17-position keto group in dl-11.alpha.-methyl-8.alpha.-oestrone methyl ether prepared according to claim 16 to a hydroxy group whereby obtaining dl-11.alpha.-methyl-8.alpha.-oestradiol methyl ether, resolving the dl methyl ether into optical isomers to obtain ent-11.alpha.-methyl-8.alpha.-oestradiol methyl ether with negative optical polarity, if required esterifying the thus prepared diol monoether to obtain an ester thereof with 1 to 18 C atoms in the acyl moiety, if required hydrolytically removing the 3-methyl group of the thus prepared ent-11.alpha.-methy1-8.alpha.-oestradiol methyl ether to obtain ent-11.alpha.-methyl-8.alpha.-oestradiol, if required esterifying at least one hydroxy group of the thus prepared ent11.alpha.--methyl-8.alpha.-oestradiol to obtain an ester of ent-11.alpha.-methyl-8.alpha.-oestradiol with 1 to 18 C atoms in the acyl moiety.
23. Ent-11.alpha.-methyl-8.alpha.-oestradiol, methyl ester thereof, an ester of the methyl ether thereof with 1 to 18 C atoms in the acyl moiety or an ester of the diol with 1 to 18 C atoms in the acyl moiety, whenever prepared or produced by the process of claim 22 or by an obvious chemical equivalent thereof.
24. A process for producing dl-11.alpha.-ethyl-8.alpha.-oestrone methyl ether, which process comprises treating dl-3-methoxy-11.alpha.-ethyl-17-methyl-13.alpha.-,17.alpha.-epoxy-8.alpha.-gona-1,3,5(10)-triene with an aprotic Lewis acid.
25. dl-11.alpha.-Ethyl-8.alpha.-oestrone methyl ether, whenever prepared or produced by the process of claim 24 or by an obvious chemical equivalent thereof.
26. A process for producing dl-11.alpha.-ethyl-8.alpha.-oestradiol or an ester thereof with 1 to 18 C atoms in the acyl moiety, which process comprises:
reducing the 17-position keto group in dl-11.alpha.-ethyl-8.alpha.-oestrone methyl ether prepared according to claim 24 to a hydroxy group whereby obtaining dl-11.alpha.-ethyl-8.alpha.-oestradiol 3-methyl ether, hydrolytically removing the 3-methyl group to obtain dl-11.alpha.-ethyl-8.alpha.-oestradiol, and if required esterifying at least one hydroxy group in the diol to obtain an ester thereof.
reducing the 17-position keto group in dl-11.alpha.-ethyl-8.alpha.-oestrone methyl ether prepared according to claim 24 to a hydroxy group whereby obtaining dl-11.alpha.-ethyl-8.alpha.-oestradiol 3-methyl ether, hydrolytically removing the 3-methyl group to obtain dl-11.alpha.-ethyl-8.alpha.-oestradiol, and if required esterifying at least one hydroxy group in the diol to obtain an ester thereof.
27. dl-11.alpha.-Ethyl-8.alpha.-oestradiol or an ester thereof with 1 to 18 C atoms in the acyl moiety, whenever prepared or produced by the process of claim 26 or by an obvious chemical equivalent thereof.
28. A process for producing dl-l7.alpha.-ethynyl-11.alpha.-methyl-8.alpha.-oestradiol or an ester thereof with 1 to 18 C atoms in the acyl moiety, which process comprises:
(A) reacting dl-11.alpha.-methyl-8.alpha.-oestrone methyl ether prepared according to claim 16 with acetylene in the presence of an alkali metal or an alkaline earth metal compound to obtain dl-17.alpha.-ethynyl-11.alpha.-methyl-8.alpha.-oestradiol methyl ether, hydrolytically removing 3-methyl group of the thus prepared methyl ether to obtain dl-17.alpha.-ethynyl-11.alpha.-methyl-8.alpha.-oestradiol, and if required esterifying at least one hydroxy group in the thus obtained free diol to obtain an ester thereof with 1 to 18 C atoms in the acyl moiety, or (B) treating dl-3-acyloxy-11.alpha.,17-dimethyl-13.alpha.,17.alpha.-epoxy-8.alpha.-gona-1,3,5(10)-triene having 1 to 18 C atoms in the acyl moiety with an aprotic Lewis acid to obtain dl-3-acyloxy-11.alpha.-methyl-8.alpha.-oestrone, reacting the thus prepared dl-3-acyloxy-11.alpha.-methyl-8.alpha.-oestrone with acetylene in the presence of an alkali metal or an alkali earth metal compound to obtain dl-17.alpha.-ethynyl-11.alpha.-methyl-8.alpha.-oestradiol mono 3-ester, if required hydrolytically removing the ester group to obtain dl-17.alpha.-ethynyl-11.alpha.-methyl-8.alpha.-oestradiol, if required esterifying the monoester or the free diol to obtain an ester of the monoester or of the diol.
(A) reacting dl-11.alpha.-methyl-8.alpha.-oestrone methyl ether prepared according to claim 16 with acetylene in the presence of an alkali metal or an alkaline earth metal compound to obtain dl-17.alpha.-ethynyl-11.alpha.-methyl-8.alpha.-oestradiol methyl ether, hydrolytically removing 3-methyl group of the thus prepared methyl ether to obtain dl-17.alpha.-ethynyl-11.alpha.-methyl-8.alpha.-oestradiol, and if required esterifying at least one hydroxy group in the thus obtained free diol to obtain an ester thereof with 1 to 18 C atoms in the acyl moiety, or (B) treating dl-3-acyloxy-11.alpha.,17-dimethyl-13.alpha.,17.alpha.-epoxy-8.alpha.-gona-1,3,5(10)-triene having 1 to 18 C atoms in the acyl moiety with an aprotic Lewis acid to obtain dl-3-acyloxy-11.alpha.-methyl-8.alpha.-oestrone, reacting the thus prepared dl-3-acyloxy-11.alpha.-methyl-8.alpha.-oestrone with acetylene in the presence of an alkali metal or an alkali earth metal compound to obtain dl-17.alpha.-ethynyl-11.alpha.-methyl-8.alpha.-oestradiol mono 3-ester, if required hydrolytically removing the ester group to obtain dl-17.alpha.-ethynyl-11.alpha.-methyl-8.alpha.-oestradiol, if required esterifying the monoester or the free diol to obtain an ester of the monoester or of the diol.
29. dl-17.alpha.-Ethynyl-11.alpha.-methyl-8.alpha.-oestradiol or an ester thereof with 1 to 18 C atoms in the acyl moiety, whenever prepared or produced by the process of claim 28 or by an obvious chemical equivalent thereof.
30. A process for producing dl-11.alpha.-methyl-8.alpha.-oestra-1,3,5(10)-triene-1, 17.beta.-diol or an ester thereof with 1 to 18 C atoms in the acyl moiety, which process comprises:
treating dl-1-methoxy-11.alpha.,17-dimethyl-13.alpha.17.alpha.-epoxy-8.alpha.-gona-1,3,5(10)-triene with an aprotic Lewis acid to obtain dl-1-methoxy-11.alpha.-methyl-8.alpha.-oestra-1,3,5(10)-triene-17-one, reducing the 17-position keto group in the thus prepared ketone to obtain dl-11.alpha.-methyl-8.alpha.-oestra-1,3,5(10)triene-1,17.beta.-diol 1-methyl ether, hydrolytically removing the 1-methyl group to obtain dl-11.alpha.-methyl-8.alpha.-oestra-1,3,5(10)-triene-1,17.beta.-diol, and if required esterifying at least one hydroxy group of the thus prepared free diol.
treating dl-1-methoxy-11.alpha.,17-dimethyl-13.alpha.17.alpha.-epoxy-8.alpha.-gona-1,3,5(10)-triene with an aprotic Lewis acid to obtain dl-1-methoxy-11.alpha.-methyl-8.alpha.-oestra-1,3,5(10)-triene-17-one, reducing the 17-position keto group in the thus prepared ketone to obtain dl-11.alpha.-methyl-8.alpha.-oestra-1,3,5(10)triene-1,17.beta.-diol 1-methyl ether, hydrolytically removing the 1-methyl group to obtain dl-11.alpha.-methyl-8.alpha.-oestra-1,3,5(10)-triene-1,17.beta.-diol, and if required esterifying at least one hydroxy group of the thus prepared free diol.
31. dl-11.alpha.-Methyl-8.alpha.-oestra-1,3,5(10)-triene-1,17.beta.-diol,or an ester thereof with 1 to 18 C atoms in the acyl moiety, whenever prepared or produced by the process of claim 30 or by an obvious chemical equivalent thereof.
32. A process for producing dl-11.alpha.-ethyl-8.alpha.-oestra-1,3,5(10)-triene-1,17.beta.-diol or an ester thereof with 1 to 18 C atoms in the acyl moiety, which process comprises:
(A) treating dl-11.alpha.-ethyl-1-methoxy-17-methyl-13.alpha.,17.alpha.-epoxy-8.alpha.-gona-1,3,5(10)-triene with an aprotic Lewis acid to obtain dl-11.alpha.-ethyl-1-methoxy-8.alpha.-oestra-1,3,5(10)-triene-17-one, reducing the 17-position keto group in the thus prepared trienone to obtain dl-11.alpha.-ethyl-8.alpha.-oestra-1,3,5(10)-triene-1,17.beta.-diol 1-methyl ether, hydrolytically removing the 1-methyl group to obtain free dl-11.alpha.-ethyl-8.alpha.-oestra-1,3,5(10)-triene-1,17.beta.-diol, if required esterifying at least one hydroxy group in the thus prepared free diol to obtain an ester thereof, or (B) treating dl-11.alpha.-ethyl-1-acyloxy-17-methyl-13.alpha.,17.alpha.-epoxy-8.alpha.-gona-1,3,5(10)-triene having 1 to 18 C atoms in the acyl moiety with an aprotic Lewis acid to obtain dl-ll-ethyl-l-acyloxy-8.alpha.-oestra-1,3,5(10)-triene-17-one, reducing the 17-position keto group in the thus prepared trienone to obtain free dl-11.alpha.-ethyl-8.alpha.-oestra-1,3,5(10)-triene-1, 17.beta.-diol, and if required esterifying at least one hydroxy group of the free diol to obtain an ester thereof.
(A) treating dl-11.alpha.-ethyl-1-methoxy-17-methyl-13.alpha.,17.alpha.-epoxy-8.alpha.-gona-1,3,5(10)-triene with an aprotic Lewis acid to obtain dl-11.alpha.-ethyl-1-methoxy-8.alpha.-oestra-1,3,5(10)-triene-17-one, reducing the 17-position keto group in the thus prepared trienone to obtain dl-11.alpha.-ethyl-8.alpha.-oestra-1,3,5(10)-triene-1,17.beta.-diol 1-methyl ether, hydrolytically removing the 1-methyl group to obtain free dl-11.alpha.-ethyl-8.alpha.-oestra-1,3,5(10)-triene-1,17.beta.-diol, if required esterifying at least one hydroxy group in the thus prepared free diol to obtain an ester thereof, or (B) treating dl-11.alpha.-ethyl-1-acyloxy-17-methyl-13.alpha.,17.alpha.-epoxy-8.alpha.-gona-1,3,5(10)-triene having 1 to 18 C atoms in the acyl moiety with an aprotic Lewis acid to obtain dl-ll-ethyl-l-acyloxy-8.alpha.-oestra-1,3,5(10)-triene-17-one, reducing the 17-position keto group in the thus prepared trienone to obtain free dl-11.alpha.-ethyl-8.alpha.-oestra-1,3,5(10)-triene-1, 17.beta.-diol, and if required esterifying at least one hydroxy group of the free diol to obtain an ester thereof.
33. dl-11.alpha.-Ethyl-8.alpha.-oestra-1,3,5(10)-triene-1,17.beta.-diol or an ester thereof with 1 to 18 C atoms in the acyl moiety, whenever prepared or produced by the process of claim 32 or by an obvious chemical equivalent thereof.
34. A process for producing dl-11.alpha.-methyl-8.alpha.-oestra-1,3,5(10) -triene-1,3,17.beta.-triol or an ester thereof with 1 to 18 C atoms in the acyl moiety, which process comprises:
treating dl-1,3-dimethoxy-11.alpha.,17-dimethyl-13.alpha.,17.alpha.-epoxy-8.alpha.-gona-1,3,5(10)-triene with an aprctic Lewis acid to obtain dl-1,3-dimethoxy-11.alpha.-methyl-8.alpha.-oestra-1,3,5(10)-triene-17-one reducing the 17-position keto group in the thus prepared trienone to obtain dl-1,3-dimethoxy-11.alpha.-methyl-8.alpha.-oestra-1,3,5(10)-triene-17.beta.-ol, hydrolytically removing the 1,3-position methyl groups to obtain free dl-11.alpha.-methyl-8.alpha.-oestra-1,3,5(10)-triene-1,3, 17-triol, and if required esterifying at least one hydroxy group of the free triol to obtain an ester thereof.
treating dl-1,3-dimethoxy-11.alpha.,17-dimethyl-13.alpha.,17.alpha.-epoxy-8.alpha.-gona-1,3,5(10)-triene with an aprctic Lewis acid to obtain dl-1,3-dimethoxy-11.alpha.-methyl-8.alpha.-oestra-1,3,5(10)-triene-17-one reducing the 17-position keto group in the thus prepared trienone to obtain dl-1,3-dimethoxy-11.alpha.-methyl-8.alpha.-oestra-1,3,5(10)-triene-17.beta.-ol, hydrolytically removing the 1,3-position methyl groups to obtain free dl-11.alpha.-methyl-8.alpha.-oestra-1,3,5(10)-triene-1,3, 17-triol, and if required esterifying at least one hydroxy group of the free triol to obtain an ester thereof.
35. dl-11.alpha.-Methyl-8.alpha.-oestra-1,3,5(10)-triene-1,3,17.beta.-triol or an ester thereof with 1 to 18 C atoms in the acyl moiety, whenever prepared or produced by the process of claim 34 or by an obvious chemical equivalent thereof.
36. A process for producing 11.alpha.-methyl-8.alpha.-oestra-1,3,5(10)-triene-1,3,17.beta.-triol or an ester thereof with 1 to 18 C atoms in the acyl moiety, which process comprises:
treating dl-1,3-dimethoxy-11.alpha.,17-dimethyl-13.alpha.,17.alpha.-epoxy-8.alpha.-gona-1,3,5(10)-triene with an aprotic Lewis acid to obtain dl-1,3-dimethoxy-11.alpha.-methyl-8.alpha.-oestra-1,3,5(10)-triene-17-one, reducing the 17-position keto group in the thus prepared trienone to obtain dl-1,3-dimethoxy-11.alpha.-methyl-8.alpha.-oestra-1,3,5(10)-triene-17~-ol, resolving the thusobtaineddl triol dimethyl ether into optical isomers to obtain 11.alpha.-methyl-8.alpha.-oestra-1,3,5(10)-triene-1,3,17.beta.-triol 1,3-dimethyl ether, hydrolytically removing the 1,3-position methyl groups to obtain free 11.alpha.-methyl-8.alpha.-oestra-1,3,5(10)-triene-1,3,17.beta.-triol, and if required esterifying at least one hydroxy group of the free triol to obtain an ester thereof.
treating dl-1,3-dimethoxy-11.alpha.,17-dimethyl-13.alpha.,17.alpha.-epoxy-8.alpha.-gona-1,3,5(10)-triene with an aprotic Lewis acid to obtain dl-1,3-dimethoxy-11.alpha.-methyl-8.alpha.-oestra-1,3,5(10)-triene-17-one, reducing the 17-position keto group in the thus prepared trienone to obtain dl-1,3-dimethoxy-11.alpha.-methyl-8.alpha.-oestra-1,3,5(10)-triene-17~-ol, resolving the thusobtaineddl triol dimethyl ether into optical isomers to obtain 11.alpha.-methyl-8.alpha.-oestra-1,3,5(10)-triene-1,3,17.beta.-triol 1,3-dimethyl ether, hydrolytically removing the 1,3-position methyl groups to obtain free 11.alpha.-methyl-8.alpha.-oestra-1,3,5(10)-triene-1,3,17.beta.-triol, and if required esterifying at least one hydroxy group of the free triol to obtain an ester thereof.
37. 11.alpha.-Methyl-8.alpha.-oestra-1,3,5(10)-triene-1,3,17.beta.-triol or an ester thereof with 1 to 18 C atoms in the acyl moiety, whenever prepared or produced by the process of claim 36 or by an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000383672A CA1170651A (en) | 1981-08-12 | 1981-08-12 | 8.alpha.-OESTRA-1,3,5(10)-TRIENE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000383672A CA1170651A (en) | 1981-08-12 | 1981-08-12 | 8.alpha.-OESTRA-1,3,5(10)-TRIENE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1170651A true CA1170651A (en) | 1984-07-10 |
Family
ID=4120671
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000383672A Expired CA1170651A (en) | 1981-08-12 | 1981-08-12 | 8.alpha.-OESTRA-1,3,5(10)-TRIENE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1170651A (en) |
-
1981
- 1981-08-12 CA CA000383672A patent/CA1170651A/en not_active Expired
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