WO1998004578A1 - Method of producing 3-sulfanato-oxy-estra-1,3,5(10)-trien derivates (i) - Google Patents

Abstract

The invention concerns a method of producing 3-sulfanato-oxy-estra-1,3,5(10)-trien derivates of the general formula (I) where the bonds marked with --- symbolize three single bonds, two single bonds and a double bond or two conjugated double bonds, X means a carbonyl group, and hydroxy-methylene group, an alkoxy-methylene group with two to six carbon atoms in the alkoxy residue, a benzyl oxymethylene group, an acyl oxymethylene group with up to eight carbon atoms in the acyl residue or an alkylene dioxymethylene group with two to six carbon atoms in the alkylene residue, and Z+ represents an alkali-metal cation, a pyridinium cation, or a piperazinium cation, by reacting a 3-hydroxy-estra-1,3,5(10)-trien derivate in the absence of catalysts with a sulphur trioxide-pyridine complex, and converting the corresponding pyridinium salt obtained, if required, into the alkali-metal salts or piperazinium salts of the general formula (I) by the action of alkali-metal bases of piperazine.

Description

 Process for the preparation of 3-sulfanato-oxy-estra-l, 3,5 (10) -triene-

Derivatives I

The invention relates to a process for the preparation of 3-sulfanato-oxy-estra-l, 3,5 (10) -triene derivatives of the general formula I.

woπn

the bonds marked with three single bonds, two

Single bonds and a double bond or two conjugated double bonds symbolize, X represents a carbonyl group, a hydroxyethylene group, an alkoxymethylene group with 2 to 6 carbon atoms in the alkoxy radical, a benzyloxymethylene group, an acyloxymethylene group with a maximum of 8 carbon atoms in the acyl radical or an alkylenedioxymethylene group with 2 to 6 carbon atoms in the alkylene radical and Z + represents an alkali metal cation or a piperazinium cation, a 3-hydroxy-estra-1,3,5 (10) -triene derivative of the general formula II

in which and X have the same meaning as in formula I, in the absence of catalysts with a sulfur trioxide-pyridine complex and optionally the pyridinium salt of general formula I a

where and X have the meaning given above, by the action of

Alkali metal bases or piperazine converted into the alkali metal salts or piperazinium salts of the general formula I.

As is known, the alkali metal salts of the general formula I are pharmacologically active substances which are referred to as conjugated estrogens (Pharmacopeia / Forum May, June 1991, p 1951-1962 and J. of Chromatography 224, 1981, p 355-370 and 224, 1982, p 234-239).

According to the known prior art, these conjugated estrogens are prepared from the 3-hydroxy-estra-1,3,5 (10) -triene derivatives of the general formula II in such a way that they are mixed with a sulfur trioxide in the presence of sodium hydride. Reacts pyridine complex (US Pat. Nos. 3,391, 169, 5,210,081 and 5,288,717). The pyridinium salts of the general formula I a are also formed intermediately in this synthesis, but are converted directly into the corresponding sodium salts of the general formula I under the conditions of the previously known process.

However, this known method has the disadvantage that it often forms considerable proportions of by-products. The formation of by-products is particularly pronounced if 3-hydroxyestra, 3,5 (10) -triene derivatives of the general formula II are used as starting compounds which have isolated double bonds in the B ring of the steroid, such as, for example, equilin. Many by-products are formed here, the double bond is easily shifted and thus the process products are disproportionated. In contrast, the process according to the invention has the advantage that it runs with fewer by-products, so that, as a rule, purer process products can be obtained in large-scale processes without expensive cleaning operations in higher yields.

It has long been known that 3-hydroxysteroids can be converted into the corresponding pyridinium salts of the corresponding 3-sulfate oxysteroids in the absence of catalysts with a sulfur trioxide-pyridine complex (J. Biol. Ch., 115, 1936, 391 ff and J. Amer. Chem. Soc., 1941, 1259 ff).

However, this process has never been used to produce conjugated estrogens, obviously because it is more complex to carry out and the person skilled in the art could not have expected that much purer process products can be obtained in this way.

As will be explained below, the piperazinium salts of the general formula I are also valuable intermediates for the production of conjugated estrogens. In addition, they are themselves pharmacologically active compounds of the same activity as the conjugated estrogens; for example, the estropipate (the piperazinium salt of 3-sulfateoxy-estra-1,3,5 (10) -tπen-17-ens).

The process according to the invention is carried out under conditions which are known per se to the person skilled in the art.

For example, the reaction of 3-hydroxy-estra-1,3,5 (10) -triene-

Carry out derivatives of the general formula II with a sulfur trioxide-pyridine complex by dissolving or suspending the sulfur trioxide-pyridine complex in a solvent which is inert to this reagent, with the 3-hydroxy-estra-1,3,5 ( 10) -triene derivative of the general formula II and optionally with stirring at - 25 ° C to 50 ° C (for simplicity at

Room temperature) until completion or implementation. Suitable inert solvents for this reaction are, for example, polar ethers, such as dioxane, 1,2-dimethoxyethanol or, in particular, tetrahydrofuran. The optimum reaction time is determined in a manner known per se using customary analysis, for example by means of thin-layer or gas chromatography. It is usually 30 minutes to 2 hours. The crystallized pyridinium salt of the general formula Ia can be used directly for further reaction after being filtered off and, if necessary, washed. The pyridinium salts are also converted into the corresponding piperazinium salts in a manner known per se by refluxing them with piperazine or an alcoholic solution of piperazine. Suitable alcohols are preferably methanol, ethanol or isopropanol. After the reaction has taken place, the pyridine released, the excess piperazine and optionally also the alcohol are eliminated by distillation and the crude product obtained is recrystallized from a suitable solvent, such as, for example, one of the abovementioned lower alcohols.

For conversion of the pyridinium salts of the general formula Ia in the conjugated ^estrogens' are suitably reacted in such a lower alcohol as the solvent with alkali metal bases, preferably lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate. This reaction is preferably carried out by heating the reaction mixture under reflux. After the reaction has taken place, the solvent and the pyridine formed are removed by distillation and the product obtained is now crystallized, for example by adding a solvent of low polarity, for example an ether such as diethyl ether or di-tert-butyl ether, to the distillation residue.

The piperazinium salts of the general formula I can also be converted into the conjugated estrogens in the same way. This procedure can be advantageous in spite of the increased effort, since this often results in purer process products than when the pyridinium salts themselves are used to prepare the conjugated estrogens.

The invention also includes a process for the preparation of 3-sulfaoxy-estra-l, 3,5 (10) -triene derivatives of the general formula I, where there is a phenolic hydroxyl in the 3-position and a secondary aliphatic

Hydroxyl group in the 17-position in the steroid uses the higher acidity of the phenol to produce the 3-phenolate anion, which then reacts preferentially with the pyridine-Sθ3 complex and thus results in a selective esterification of only the 3-hydroxy group. Sodium methylate is advantageously used as the base. The following exemplary embodiments serve to explain the method according to the invention in more detail.

Example \ a) To a suspension of 7.0 g of pyridine-sulfur trioxide complex (Aldrich Chem. Comp. Inc., Milwaukee USA; LF Fieser and M. Fieser, Reagents for Organic Synthesis, John Wiley and Sons, Inc. New York et al. i, 1127 and 1128, 2, 393 - 394, 3_, 275 - 276) in 160 ml of anhydrous tetrahydrofuran are added in a nitrogen atmosphere at room temperature 10.0 g of 3-hydroxy-estra-l, 3.5 (10) -trien- 17-one and stir for one hour at room temperature. Then 0.3 ml of water is added dropwise to the reaction mixture, the mixture is stirred for a further 15 minutes and cooled to 0.degree.

The mixture is left to stand at 0 ° C. for 15 minutes, the pyridinium salt is filtered off and washed with a little cold tetrahydrofuran.

b) The finely crystalline substance prepared according to Example 1a is added to a solution of 4.0 g of sodium hydroxide in 150 ml of methanol, heated under reflux for 30 minutes and then concentrated in vacuo. Then methanol is added several times and the mixture is concentrated in vacuo in order to remove the released pyridine. The reaction mixture is then mixed with ethanol, concentrated in vacuo, cooled to room temperature and mixed with 200 ml of methyl tert-butyl ether. The precipitated 3-sulfanato-oxy-estra-1,3,5 (10) -trien-3-one is filtered off with suction, washed with a little methyl tert-butyl ether and dried in a vacuum drying cabinet. This gives 14.0 g of crude product which is mixed with 0.5 g of sodium acetate in 24 ml of absolute ethanol and stirred at 50 ° C. for one hour. The mixture is then cooled to 10 ° C., filtered, washed with a little absolute ethanol and dried.

This gives 12.6 g of pure product which contains 5% sodium acetate as stabilizer.

[ _α ] 20 = + 95.0 ° (c = 1 / in water) Example 2:

100.0 g of pyridine-sulfur trioxide complex are suspended in 35 ml of pyridine and 800 ml of tetrahydrofuran, and 100.0 g of 17α-acetoxy-estra-1,3,5 (10) -trien-3-ol are added. The reaction mixture is stirred for 4 hours at room temperature, cooled to 10 ° C., the precipitated crystals are filtered off and washed with 100 ml of cold tetrahydrofuran.

The pyridinium salt thus obtained (160.0 g) is added to a solution of 35 g of sodium hydroxide in 1950 ml of methanol and the mixture is heated under reflux for 30 minutes. Then 500 ml of solvent mixture are distilled off, 500 ml of methanol are added and 500 ml of mixture are distilled off again.

This process is repeated a number of times, then cooled to room temperature without distillation residue, and 22.4 ml of glacial acetic acid and 6000 ml of methyl tert-butyl ether are added. After standing for 2 hours at room temperature, the precipitated crystalline is filtered off and washed with 100 ml of methyl tert-butyl ether. The product obtained in this way is dried in a vacuum drying cabinet at 30 ° C., and 117 g of the sodium salt of 3-sulfanato-oxy-estra-l, 3,5 (10) -trien-17α-ol, which is about 7% sodium acetate, are obtained Contains stabilizer.

Mp .: 151-152 ° C

Example 3: 90.0 g of pyridine-sulfur trioxide complex are suspended in 800 ml of tetrahydrofuran. Then 100.0 g of 3-hydroxy-estra-1,3,5 (10) -triene-17-one are added to the suspension, the mixture is stirred at 20 ° C. for 30 minutes, the mixture is cooled to 0 ° C. and the resulting mixture is filtered Pyridinium salt and washes it with 50 ml of cold tetrahydrofuran.

The pyridinium salt thus obtained is dissolved in a solution of 184.0 g of piperazine

Hexahydrate introduced into 1200 ml of methanol and heated under reflux for 45 minutes, 450 ml of pyridine / methanol mixture being distilled off. The remaining pyridine is then removed by vacuum distillation at an internal temperature of 45 ° C. with repeated additions of methanol. Finally, the mixture is concentrated to 440 ml, cooled to -15 ° C and the precipitated crystals are filtered off. It is dried in a forced-air cabinet in a vacuum and 151.0 g of the piperazinium salt of 3-sulfatoxy-estra-1,3,5 (10) -trien-17-one are obtained.

20 [α] £> = + 88 ° (c = 1 / in 1% aqueous sodium hydroxide solution)

Example 4:

A suspension of 17.5 g of pyridine-sulfur trioxide complex in 200 ml of anhydrous tetrahydrofuran is cooled to 0 ° C., 25.0 g of Estra-l, 3.5 (10) -tetraen-3.17α-diol are added, and 3 Stirred for hours while the reaction mixture warmed to room temperature. Then 500 ml of methyl tert-butyl ether are added to the mixture, the pyridinium salt is filtered off and washed with methyl tert-butyl ether.

The pyridinium salt obtained is introduced into a solution of 46.0 g of piperazine hexahydrate in 950 ml of methanol, heated to 45 ° C. and the solvents and the pyridine are removed by vacuum distillation, these being replaced several times by the addition of methanol and then ethanol. The residue is recrystallized from ethanol and 20.0 g of piperazinium salt of 3-sulfatoxy-estra-l, 3,5 (10) -7-tetraen-17α-ol are obtained.

[ ^α l D ^{= +} H5.6 ° (c = 1 / in 50% aqueous methanol)

Example 5: Under the conditions of Example 4, but using 25.0 g of 3-hydroxy-estra-1, 3.5 (10), 8-tetraen-17-one, 26.5 g of piperazinium salt of 3-sulfatoxy -estra- 1, 3.5 (10), 8-tetraen-17-one prepared.

Mp 202-208 ° C

Example 6:

7.2 g of sodium carbonate and XXX ml of methanol are added to 25.0 g of the piperazinium salt of 3-sulfatoxy-estra-l, 3,5 (10) -trien-17-one, and the mixture is heated to 50 ° C. and the methanol is distilled off in vacuo . Methanol and later ethanol are then added several times and the mixture is distilled off in vacuo. 21.5 g of sodium salt of 3-sulfatoxy-estra-1,3,5 (10) -trien-17-one are thus obtained.

10

[α] _D = 95.5 ° (c = 1 / in water)

Claims

Claims: 1. Process for the preparation of 3-sulfaoxy-estra-1,3,5 (10) -triene derivatives of the general formula I.

wherein the bonds marked with three single bonds, two Symbolize single bonds and a double bond or two conjugated double bonds, X is a carbonyl group, a hydroxymethylene group, an alkoxymethylene group with 2 to 6 carbon atoms in the alkoxy radical, a benzyloxymethylene group, an acyloxymethylene group with a maximum of 8 carbon atoms in the acyl radical or one Alkylenedioxymethylengruppe with 2 to 6 carbon atoms in the alkylene radical means and Z ^{+ represents} an alkali metal cation or a piperazinium cation, characterized in that a 3-hydroxy-estra-1,3,5 (10) -triene derivative of the general formula II (π)

wherein and x have the same meaning as in formula I, in the absence of catalysts with a sulfur trioxide-pyridine complex and optionally the pyridinium salt of general formula I a obtained

wherein and X have the meaning given above, by the action of alkali metal bases or piperazine converted into the alkali metal salts or piperazinium salts of the general formula I. 2. Process for the preparation of 3-sulfaoxy-estra-1,3,5 (10) -triene derivatives of the general formula I b

wherein the bonds marked with three single bonds, two Symbolize single bonds and a double bond or two conjugated double bonds, X is a carboxyl group, a hydroxymethylene group, an alkoxymethylene group with 2 to 6 carbon atoms in the alkoxy radical, a benzyloxymethylene group, one Acyloxymethylene group with a maximum of 8 carbon atoms in the acyl radical or one Alkylenedioxymethylengruppe with 2 to 6 carbon atoms in the alkylene radical means and Z '+ represents an alkali metal cation, characterized in that the corresponding piperazinium salt of the general formula I is converted into the alkali metal salts by the action of alkali metal bases. 3. A process for the preparation of 3-sulfaoxy-estra-l, 3,5 (10) -triene derivatives of the general formula I, characterized in that in the presence of a phenolic hydroxyl in the 3-position and a secondary aliphatic hydroxyl group 17-position in the steroid uses the higher acidity of the phenol to selectively produce the 3-phenolate anion, which then reacts preferentially with the pyridine-SOSS complex and thus results in a selective esterification of the 3-hydroxy group.