WO1995029931A1 - METHOD FOR STEREOSELECTIVE INSERTION OF AN ALKYNYL SIDE CHAIN IN 11β-ARYL SUBSTITUTED 13α-ALKYLGONAN-17-ONES - Google Patents

Abstract

Described is a method for stereoselective insertion of an alkynyl side chain - -R2, where R2 is a hydrogen atom, a methyl group or a hydroxymethyl group in which the hydroxy group is protected, in the 17β-position of a 13α-alkylgonan-17-one of general formula (I), wherein Y is a protected keto function in the form of a ketal or a thioketal, R1 is a hydrogen atom, a methoxy, thiomethoxy, dimethylamino or other group known to be a substituent of the 11β-phenyl substituent in competitive progesterone antagonists, and R13 is a methyl or ethyl group, the nucleophilic addition of the lithiated alkine Li- -R2 on the 17-keto group being done with the addition of 1 to 10 equivalents of a lithium salt such as lithium chloride, bromide or perchlorate. This results in a marked improvement in the stereoselectivity of the addition reaction and in increased yield.

Description

 Process for the stereoselective introduction of an alkynyl side chain to llß-aryl-substituted 13α-alkylgonan-17-ones

The present invention relates to a process for the stereoselective introduction of an alkynyl side chain - = - R ² , in which R ² denotes a hydrogen atom, a methyl group or a hydroxymethyl group in which the hydroxyl group is protected, in the 17β position of a 13α-alkyl-gonane -17-ons of the general formula I

wonn

Y is a keto function protected in the form of a ketal or thioketal,

R ^{1 is} a hydrogen atom, a methoxy, thiomethyl, dimethylamino or another group known as a substituent of the 11β-phenyl substituent in competitive progesterone antagonists, and

R ^{13 is} a methyl or ethyl group

mean by nucleophilic addition of the lithiated alkyne Li-≡-R ² to the 17-keto group. IIß-Aryl-substituted 13α-alkylgonanes are highly effective competitive antagonists of the hormone progesterone. The first and most prominent representative of these 13-retrosteroids is llß- (4-dimethylaminophenyl) -17α-hydroxy-17ß- (3-hydroxypropyl) -13α-methyl-4,9-gonadien-3-one (onapristone) (EP -A 0 129 499; Steroids 1984. 349). Further such progesterone antagonists with a 13α-alkyl group can be found, for example, in European Patent 0 186 834 and European Patent Application 0 349 481. Because of their strong affinity for the progesterone receptor, these compounds are able to displace the progesterone from its receptor and thus prevent the progesterone effect. They are therefore suitable for the treatment of hormone-dependent tumors, for example breast cancer, and for influencing progesterone-dependent conditions or processes. Competitive progesterone antagonists can thus be used for induction of birth, termination of pregnancies (both preferably in combination with a prostaglandin or with oxytocin) or for implantation inhibition (female fertility control).

In addition to their substituted 11β-aryl substituent, the structures of these antagonists are distinguished by a saturated or unsaturated, optionally substituted, hydrocarbon side chain on the carbon atom 17 of the steroid skeleton which generally has at least 3 carbon atoms.

This so-called C-17 side chain (or its precursor) is introduced by adding a deprotonated alkyne, preferably a lithiated propargyl-THP ether (THP = tetrahydropyranyl radical as a protective group for the hydroxyl group) to a corresponding 17-ketone.

In contrast to the introduction of such a C-17 side chain on a 13β-alkyl-gonan-17-one derivative, the nucleophilic attack of a lithiated alkyne on the 17-keto group of a 13α-alkyl-gonan-17-one does not take place satisfactory stereoselectivity (EP-A-0 129 499; Steroids 1984, 349). In addition to the desired 17ß addition product, there is also a considerable amount of addition product which has the substituted substituent in the 17α position. A further limitation of the known process is the incomplete conversion of the 13α-alkyl-gonan-17-one despite a large excess of alkyne to be added. The reason for this is the existence of a cis-hydrindanone system in which the 17-keto group is shielded from both sides to a comparable extent. In addition to the addition reaction, deprotonation to the enolate also takes place. The resulting 17-epimer and unreacted starting material have to be separated from the desired product by expensive column chromatography.

(I) (IIa): M = OH; N = ≡-R ²

(Ilb): M = -_- R ² ; N = OH

The object of the present invention is to provide a method for the stereoselective introduction of C-17-alkynyl sites in the β-position on 13α-alkyl-gonan-17-ones. At the same time, the most complete possible conversion of the starting product would be desirable.

This object is achieved by providing the process according to the invention of the type specified at the outset, in which the lithiated alkyne is added to the compound of the general formula I with the addition of a lithium salt.

In the context of the present invention, Y denotes a common ketal protective group, for example the ethylenedioxy or the 2,2-dimethylpropylene-1,3-dioxy group. Other common keto protection groups are also considered. Y can also mean a protected hyα oxygπippe and a hydrogen atom, the hydroxyl group then being protected, for example, as methoxymethyl, methoxyethyl, tetrahydropyranyl or silyl ether. Splitting off the protective group and oxidation of the free hydroxy group leads to the keto group. If a terminal, protected hydroxyl group is present in R ² , the tetrahydropyranyl radical, for example, is well suited as a protecting group.

It has been found that the addition of a lithium salt surprisingly brings about a significant increase in the stereoselectivity of the nucleophilic addition of the lithiated alkyne Li-≡-R ² to a compound of the general formula I.

In addition, the otherwise observed enolization of the 17-keto function is suppressed and a complete conversion is thereby achieved.

So far, it was only known that lithium salts can be used to minimize the excess of the alkynyllithium compound required for nucleophilic addition of alkynyllithium compounds to 17-ketosteroids with a natural 13β configuration (WO-A 93/15103) and that lithium perchlorate can reduce the Stereoselectivity of the addition of methyl lithium to certain ketones improved (A. Loupy and B. Tchoubar in: Salt Effects in Organic and Organometallic Chemistry, VCH, Weinheim, 1992, p. 156).

The improvement of the stereoselectivity in the addition of an alkynyl lithium compound to a 13α-alkyl-gonan-17-one and the suppression of the enolization of the 17-keto group were not expected.

The 17α-hydroxyisomers formed and desired can be isolated after chromatography over aluminum oxide in very high yields of over 85%. The ratio of the desired 17α-hydroxyisomer to 17ß-hydroxyisomer also formed is between 7: 1 and 10: 1.

Without the addition of a lithium salt according to the invention in the nucleophilic addition of the lithiated alkyne, its entry into the 17 position proceeds only with moderate stereo selectivity (17α-OH / 17β-OH is approximately 3: 1); in addition, despite the use of a large excess of the alkyne to be added, the reaction mixture still contains approximately 10% of the starting material of the general formula I.

In a preferred embodiment of the process according to the invention, the liter alkyne is added with the addition of 1 to 10 equivalents of the lithium salt, based on the compound of the general formula I. All common inorganic lithium salts are suitable as the lithium salt; Lithium chloride, bromide and perchlorate are particularly suitable.

The lithium salt can be added to the (to be added) alkyne H-≡-R ² before or after its deprotonation with an alkyl lithium compound such as methyl, ethyl, propyl or butyllithium to form the reactive species Li-sR ² .

In the form of the commercially available complex CH ₃ Li-LiBr, the lithium salt can also be brought along with the deprotonation reagent. This joint use of deprotonating agent and lithium salt in a complex compound allows a much easier and safer handling of the pure, flammable deprotonating agent methyl lithium. The complex compound mentioned is also cheaper than the salt-free methyl lithium.

The addition reaction can be carried out in ethereal solvents; as such, especially tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane or mixtures of these solvents can be mentioned.

The reaction temperature for the addition reaction of the alkyne should be between -70 and +20 ° C.

The compounds of the general formula Ha (and also those of the general formula IIb) prepared by the new process can be processed further to known biologically active competitive progesterone antagonists by known processes (EP-A 0 129 499; Steroids 1984, 349).

The 17β-hydroxyisomers of the general formula IIb which have hitherto been produced when C-17-alkynyl side chains are introduced - and also in the process according to the invention in small amounts - have hitherto not been able to be used to prepare the more valuable 17α-hydroxyisomers of the general formula Ha.

It has now been found that, by the action of a strong base on a compound of the general formula IIb, its 17α-side chain is surprisingly cleaved in very high yield, with the corresponding IT ^ ketone of the general formula I being formed. 6 -

(Ilb) (I)

The reaction proceeds with bases such as Na or KH, Na or K amide, Na or K alcoholates in an organic solvent such as THF, dimethoxyethane, diethyl ether, dioxane or mixtures thereof (preferably with NaH in THF). The 17-keto compounds recovered in 80 - 90% yield after chromatographic purification can be reused for a new side chain introduction.

The following examples serve to explain the invention in more detail:

example 1

llß- (4-dimethylaminophenyl) -3,3- (2,2-dimethylpropane-1,3-dioxy) -13α-methyl-17α- [3- (tetrahydropyran-2-yloxy) -l-propynyl] -9- gonen-5α, 17ß-diol llß- (4-dimethylaminophenyl) -3,3- (2,2-dimethylpropan-l, 3-dioxy) -13α-methyl-17ß- [3- (tetrahydropyran-2-yloxy) - l-propynyl] -9-gonen-5α, 17α-diol

To a solution of 39.7 g 3-propinol-THP (tetrahydropyranyl) ether in 200 ml MTB (methyl tert-butyl ether) at -15 ° C 129 ml MeLi-LiBr (methyl lithium lithium bromide) complex (6% solution in Diethyl ether) added dropwise. A solution of 13.4 g of 11ß- (4-dimethylaminophenyl) -3.3- (2,2-dimethylpropan-l, 3-dioxy) -5α-hydroxy-13-methyl-9- gonen-17-one in 30 ml MTB ether slowly added. The reaction mixture is stirred for 2 hours at -25 ° C and after heating to 20 ° C for 1 hour. 400 ml of water are then added, the phases are separated and the aqueous phase is re-extracted with 100 ml of MTB ether. The combined organic phases are dried over sodium sulfate and concentrated. The oily residue is chromatographed on 1500 g of aluminum oxide (neutral, activity level II) using hexane / ethyl acetate (7: 3). In the elution order 1.53 g (8.9%) llß- (4-dimethylaminophenyl) -3.3- (2,2-dimethylpropan-l, 3-dioxy) -13-methyl-17 - [3- (tetrahydropyran-2-yloxy) -l-propynyl] -9-gonen-5, 17ß-diol and 14.79 g (86.4%) llß- (4-dimethylaminophenyl) -3,3- (2,2- Dimethylpropan-l, 3-dioxy) -13α-methyl-17ß- [3- (tetrahydropyran-2-yloxy) -l-propynyl] -9-gonen-5, 17α-diol obtained as colorless oils. The products are identical to the compounds described in EP-A-0 129 499 [Example 2b)].

Example 2

llß- (4-dimethylaminophenyl) -3,3- (2,2-dimethylpropane-1,3-dioxy) -13α-methyl-17α- [3- (tetrahydropyran-2-yloxy) -l-propynyl] -9- gonen-5, 17ß-diol llß- (4-dimethylaminophenyl) -3,3- (2,2-dimethylpropan-l, 3-dioxy) -13-methyl-17ß- [3- (tetrahydropyran-2-yloxy) - l-propynyl] -9-gonen-5α, 17α-diol

142.5 ml of BuLi (butyllithium) (1.6 molar solution in hexane) are added to a solution of 32.0 g of 3-propinol-THP ether and 21.2 g of lithium chloride in 100 ml of THF (tetrahydrofuran) at -15 ° C ) added dropwise. A solution of 15.0 g of llß- (4-dimethylaminophenyl) -3.3- (2,2-dimethylpropane-1,3-dioxy) -5α-hydroxy-13α-methyl-9- gonen-17-one in 30 ml THF slowly added. The reaction mixture is stirred for 2 hours at -20 ° C and after heating to 20 ° C for 1 hour. 600 ml of water are added and extracted three times with 300 ml of MTB ether each. The combined organic phases are dried over sodium sulfate and concentrated. The oily residue is chromatographed on 1800 g of aluminum oxide (neutral, activity level II) using hexane / ethyl acetate (7: 3). In the elution order, 2.45 g (12.7%) of llß- (4-dimethylaminophenyl) -3 , 3- (2,2-dimethylpropan-l, 3-dioxy) - 13α-methyl-17 - [3- (tetrahydropyran-2-yloxy) -l-propynyl] -9-gonen-5, 17ß-diol and 15 , 64 g (81.2%) llß- (4-dimethylaminophenyl) -3,3- (2,2-dimethylpropan-1,3-dioxy) - 13α-methyl-17ß- [3- (tetrahydropyran-2-yloxy ) -l-propynyl] -9-gonen-5α, 17α-diol obtained as colorless oils.

Recycling of the undesired 17α-alkynyl-17β-hydroxy isomers in the corresponding 17-ketone

Example 3

2.0 g llß- (4-dimethylaminophenyl) -3,3- (2,2-dimethylpropan-l, 3-dioxy) -13-methyl-17α- [3- (tetrahydropyran-2-yloxy) -l-propynyl ] -9-gons-5, 17ß-diol are refluxed with 60 mg NaH (sodium hydride) (60% suspension) in 10 ml THF for 2 hours. The reaction mixture is cooled to 20 ° C., mixed with 10 ml of saturated ammonium chloride solution and extracted three times with 20 ml of ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated. The oily residue is chromatographed on 50 g of silica gel with hexane / ethyl acetate (3: 1). 1.26 g (81.0% of theory) of llß- (4-dimethylaminophenyl) -3,3- (2,2-dimethylpropan-l, 3-dioxy) -5α-hydroxy-13α-methyl- 9-gonen-17-one obtained as a colorless oil. The product is identical to the starting material of Examples 1 and 2.

Example 4

1.2 g llß- (4-dimethylaminophenyl) -3,3- (2,2-dimethylpropane-1,3-dioxy) -13α-methyl-17α- [3- (tetrahydropyran-2-yloxy) -l-propynyl ] -9-gonen-5α, 17ß-diol are dissolved in 15 ml of MTB ether and 0.18 g of potassium tert-butoxide is added. The reaction mixture is heated under reflux for 3 hours, cooled to 20 ° C., mixed with 10 ml of saturated ammonium chloride solution and extracted three times with 20 ml of MTB ether each. The combined organic phases are dried over sodium sulfate and concentrated. The oily residue is chromatographed on 40 g of silica gel with hexane / ethyl acetate (3: 1). 0.68 g (73.0% of theory) of llß- (4-dimethylaminophenyl) -3,3- (2,2-dimethylpropane-1,3-dioxy) -5α-hydroxy-13α- methyl-9-gonen-17-one obtained as a colorless oil.

Claims

Claims 1.) Process for the stereoselective introduction of an alkynyl side chain - = - R ² , in which R ^{2 is} a hydrogen atom, a methyl group or a hydroxymethyl group in which the hydroxyl group is protected, in the 17β position of a 13α-alkyl-gonane -17-ons of the general formula I

wonn Y is a keto function protected in the form of a ketal or thioketal, R ^{1 is} a hydrogen atom, a methoxy, thiomethyl, dimethylamino or another group known as a substituent of the 11β-phenyl substituent in competitive progesterone antagonists, and R ^{13 is} a methyl or ethyl group mean by nucleophilic addition of the lithiated alkyne Li-≡-R ² to the 17-keto group, characterized in that the lithiated alkyne is added to the compound of general formula I with the addition of a lithium salt. 2.) Process according to claim 1, characterized in that the lithiated alkyne is added with the addition of 1 to 10 equivalents of the lithium salt, based on the compound of general formula I. 3.) Method according to claim 1 or 2, characterized in that the lithium salt is lithium chloride, bromide or perchlorate. ^• 4.) Method according to one of claims 1, 2 or 3, characterized in that the lithium salt to the alkyne H-≡-R ² before its deprotonation with an alkyl-lithium compound (methyl, ethyl, propyl or butyllithium) added becomes. 5.) The method according to claim 3, characterized in that the lithium salt lithium bromide is used together with the base used for the deprotonation of the alkyne H-≡-R ² methyl lithium as a complex compound MeLi-LiBr. 6.) Method according to claim 1, 2, 3, 4 or 5, characterized in that as Solvents used to carry out tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane or mixtures of these ethers. 7.) Method according to one of the preceding claims, characterized in that it is carried out at a reaction temperature of -70 to 20 ° C.