WO2011110597A1 - Method for producing strontium ranelate - Google Patents

Abstract

The invention relates to a novel method for producing strontium ranelate of formula (I) (distrontium-5-[bis(carboxymethyl)amino]-2-carboxy-4-cyanthiophene-3-acetate) and the hydrates thereof and to novel intermediates for producing same.

Description

 Process for the preparation of strontium ranelate

description

The present invention relates to a novel process for the preparation of strontium ranelate of the formula (I)

(Distrontium-5- [bis (carboxymethyl) amino] -2-carboxy-4-cyanothiophene-3-acetate) and its hydrates, and novel intermediates for their preparation. Strontium ranelate and its hydrates have valuable pharmacological and therapeutic properties and are useful for the treatment and prevention of bone diseases. They are used in particular for the treatment and prevention of osteoporosis and osteoarthritis. Strontium ranelate, the preparation and the therapeutic use of strontium ranelate and its tetrahydrate, heptahydrate and octahydrate are known from EP 0 415 850 A1.

EP 0 813 869 A1 describes the use of strontium ranelate for the treatment of osteoarthritis.

From the literature several processes for the preparation of strontium ranelate and its hydrates are known. However, these methods provide no satisfactory yields. EP 0 415 850 A1, WO 2007/020527 A2 and US 2009/0082578 A1 describe various processes for the preparation of strontium ranelate. US 2004/0063972 A1 and US 2006/0142596 A1 each describe a process for the industrial production of strontium ranelate.

The processes described in the literature for the preparation of strontium ranelate are based in principle on a two-part process: The first part of the process is the construction of the thiophene skeleton by means of Gewald reaction (Scheme 1).

Scheme 1:

Hierbei wird z.B Diethyl- oder Dimethyloxoglutarat (R= Ethyl bzw. Methyl) mit Malondinitril kondensiert und anschließend mit elementarem Schwefel unter Einfluss einer Base zum gewünschten tetrasubstituierten Thiophen umgesetzt. Das Prinzip wurde zum ersten Mal von Gewald, Schinke und Böttcher in Chemische Berichte, Jahrgang 99, Seiten 94-100 (1966) sowie in Chemische Berichte, Jahrgang 99, Seiten 2712-2715 (1966) beschrieben und später von M. Wierzbicki, D. Cagniant, P. Cagniant in Bulletin de la Societe Chimique de France, Nr. 7-8 (1975) Seiten 1786-1792 auf die oben beschriebenen Derivate angewandt.

Here, for example, diethyl or Dimethyloxoglutarat (R = ethyl or methyl) is condensed with malononitrile and then reacted with elemental sulfur under the influence of a base to the desired tetrasubstituted thiophene. The principle was first described by Gewald, Schinke and Böttcher in Chemische Berichte, volume 99, pages 94-100 (1966) and in Chemische Berichte, volume 99, pages 2712-2715 (1966) and later by M. Wierzbicki, D Cagniant, P. Cagniant in Bulletin de la Societe Chimique de France, Nos. 7-8 (1975) pages 1786-1792 applied to the derivatives described above.

The method starting from dimethyloxoglutarate (R = methyl) is described in US 2004/0063972 A1 and US 2006/0142596 A1. This is the reaction is carried out in methanol as solvent and in the presence of morpholine as base. The yields are 77% with a specified purity of 98%. The second part of the process is the conversion of the thiophene backbone to the strontium ranelate. In the processes described in EP 0 415 850 A1, this reaction is carried out by double alkylation of the amino group with a 2-haloalkyl ester, for example ethyl bromoacetate or bromoacetic acid, then saponified to the desired strontium ranelate using strontium hydroxide or sodium hydroxide followed by ion exchange using strontium chloride (Scheme 2). According to the process described in US 2009/0082578 A1, the saponification of the corresponding tetraester takes place at 20-70 ° C. Isolation of potassium ranelate prior to the ion exchange reaction with strontium chloride is possible. In US 2004/063972 A1, the alkylation is ₈ -C conducted ₀ quaternary ammonium compound in the presence of a catalytic C to reduce the response time of the alkylation to a few hours while increasing the reaction yield. According to US 2004/063972 A1, yields of 85% are obtained with a purity of> 98% for the alkylation with methyl bromoacetate.

Scheme 2:

The disadvantage of the processes described above is the formation of undesirable side reactions that occur in the alkaline saponification of the esters in the last stage, and the unsatisfactory yields of strontium ranelate. Due to acidic hydrogen atoms in the 2-position of the esters, under basic conditions not only their saponification but simultaneously also intramolecular cyclization with the nitrile group occurs. This intramolecular cyclization product leads by decarboxylation to other undesirable by-products.

These by-products can not accumulate in the strontium ranelate since strontium ranelate is almost insoluble in all organic solvents as well as in water. In order to obtain very pure strontium ranelate in high yields, the impurities must be avoided during synthesis.

According to the process described in US 2004/0063972 A1, strontium ranelate is obtained by reacting the tetraester with strontium hydroxide in a yield of 96% and a purity of> 98%.

In the process described in WO 2007/020527 A2, the saponification is described starting from the tetraester by reaction with lithium bases, such as lithium hydroxide and lithium carbonate and subsequent treatment with strontium chloride, wherein strontium ranelate in a yield of 84.6% with a purity of> 99.5 % is obtained.

The object of the present invention was therefore to provide an alternative process for the preparation of strontium ranelate and its hydrates, with which strontium ranelate and its hydrates are obtained in higher yields at high purities.

It has now been found that strontium ranelate of the formula (I) (Distrontium-5- [bis (carboxymethyl) amino] -2-carboxy-4-cyanthiophene-3-acetate) and its hydrates are obtained by a process (variant A), which comprises the following steps: a) reaction of a compound of the formula (II),

 (Ii)

in which

Ri is C 1 -C ₄ -alkyl, with malononitrile of the formula (III)

N C CN

(Hl)

and sulfur in the presence of an organic diluent and in the presence of an organic base or a heterogeneous inorganic base to give a compound of formula (IV),

(IV)

in which Ri has the meaning given above; b) reacting a compound of the formula (IV) in which R has the meaning indicated above with a compound of the formula (V)

in which X is bromine or chlorine and

R _{2 is} C 1 -C ₄ -alkyl or benzyl, in the presence of a heterogeneous base, in the presence of an organic solvent and in the presence of catalytic amounts of water, to give a compound of the formula (VI)

(VI) in which Ri and R _{2 have} the meanings given above; c) reaction of a compound of the formula (VI) in which R 1 has the abovementioned meaning and R _{2 is} C 1 -C ₄ -alkyl, with a strong organic acid, in the presence of an organic solvent to give a compound of the formula (VII) .

(VII) in which Ri has the meaning given above; and d) reacting a compound of formula (VII) in which Ri is as defined above with an alkali metal hydroxide and a strontium salt in the presence of water

Strontium ranelate of the formula (I) or its hydrates.

The compound of the formula (VI) in which R 1 is ethyl and R _{2 is} tert-butyl (compound 2) is novel and likewise the subject of the invention.

The compound of the formula (VI) in which R 1 is ethyl and R _{2 is} benzyl (compound 4) is novel and likewise the subject of the invention.

The compounds of the formula (VII) are novel and likewise the subject of the invention. Preference is given to compounds of the formula (VII) in which R 1 is ethyl.

The process steps a) and c) are independent of the overall process of variant A new and also the subject of the invention.

The process step d) is independent of the overall process of variant A new, if Ri is ethyl and also the subject of the invention.

In the definition of Ri and R ₂ , the saturated hydrocarbon chains of CC ₄ alkyl are each straight-chain or branched. In particular, C 1 -C ₄ -alkyl is preferably methyl, ethyl, n- or i-propyl, n-, sec-, i- or tert-butyl, in particular methyl, ethyl or tert-butyl.

Benzyl stands for the phenylmethyl group -CH ₂ -C ₆ H ₅ . X is bromine or chlorine, in particular bromine.

Ri is particularly preferably ethyl. R ₂ particularly preferably represents tert-butyl or benzyl.

The abovementioned preferred ranges of the radical definitions of R 1 and R ₂ apply correspondingly to the starting materials or intermediates of the formulas (II), (IV), (V), (VI), (VII) and (VIII) required for the preparation of strontium ranelate Variants A, B and C of the method according to the invention.

It is extremely surprising to note that through the use of dimethylacetamide (DMA) and an organic base such as e.g. Triethylamine the yield of Gewald reaction (step a)) significantly increased and the product can be obtained at the same time in very high purity. Thus, yields of over 85% are achieved.

Furthermore, it is surprising that in process step c) the cleavage of the ester protecting groups on the amino function under acidic conditions completely avoids the side reactions of cyclization and decarboxylation, so that - after the subsequent process step d) - very pure strontium ranelate with a purity of> 99.8% can be produced.

Variant A of the process according to the invention comprises process steps a), b), c) and d) and is shown in FIG. 1 (Ri = ethyl (Et), R ₂ = C (CH ₃ ) ₃ ). In process step a) according to the invention, the temperature can vary over a wide range. Process step a) is generally carried out at temperatures of 50 ° C to 90 ° C, preferably at temperatures of 75 ° C to 85 ° C. Suitable diluents for carrying out process step a) according to the invention are, by way of example and by way of preference, alcohols, such as ethanol or butanol; Ethers such as tetrahydrofuran or methyltetrahydrofuran; Esters, such as ethyl acetate; aromatic hydrocarbons such as chlorobenzene; polar non-protic solvents such as dimethylformamide, N-methylpyrrolidone or dimethylacetamide into consideration. The solvent dimethylacetamide (DMA) is preferably used in process step a).

Process step a) according to the invention is carried out in the presence of an organic base or a heterogeneous inorganic base. Suitable organic bases are all customary organic bases. These include, by way of example and by way of preference, tertiary amines, such as, for example, trimethylamine, triethylamine, tributylamine, N, N-dimethylethylamine, N, N-diisopropylethylamine, Ν, Ν-dimethylbenzylamine, pyridine, piperidine, N-methylpiperidine, N- Methylmorpholine, N, N-dimethylaminopyridine, N-methylethanolamine, diazabicyclooctane (DABCO), diazabicyclononene (DBN) or diazabicycloundecene (DBU). Heterogeneous inorganic bases are all heterogeneous inorganic bases. These include, by way of example and by way of preference, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate; Alkali metal bicarbonates, such as sodium bicarbonate,

Dinatriumhydrogencarbonat; Alkali metal phosphates such as potassium phosphate. In process step a), triethylamine is preferably used. The process step a) according to the invention is carried out in particular as described below. In process step a), the compound of formula (II) is dissolved in dimethylacetamide and treated with malononitrile. Subsequently, triethylamine and sulfur are added. Process step b) is generally carried out at temperatures of 40 ° C to 80 ° C, preferably at temperatures of 50 ° C to 70 ° C, more preferably at temperatures of 55 ° C to 65 ° C. Process step b) is carried out in the presence of a heterogeneous base. As such, all common heterogeneous bases are suitable. These include, by way of example and by way of preference, alkali metal carbonates, such as, for example, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate; Alkali metal bicarbonates, such as sodium bicarbonate, disodium bicarbonate; Alkali metal phosphates such as potassium phosphate. Preferably, in process step b) potassium carbonate is used. Suitable diluents for carrying out process step b) are all inert organic solvents. These include, by way of example and by way of preference, aromatic hydrocarbons, such as toluene; Ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, methyl t-amyl ether, dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, 1, 2-diethoxyethane or anisole; Nitriles such as acetonitrile, propionitrile, n- or i-butyronitrile or benzonitrile; Amides such as Ν, Ν-dimethylformamide, N-methylformanilide; chlorinated hydrocarbons such as methylene chloride; Sulfoxides such as dimethylsulfoxide; Sulfones, ketones such as acetone or methyl ethyl ketone. Preferably, in process step b) acetone or methyl ethyl ketone is used.

As catalytic amounts of water in step b) 0.1-5 eq. Water, preferably 0.2-2.5 eq. Water, more preferably 0.3-1 eq. Water used (1 eq means 1 equivalent). The method step b) is carried out in particular as described below. In process step b), the compound of formula (V) is dissolved in an organic solvent and using a heterogeneous base, for example potassium carbonate, by means of 2-haloacetic acid-ieri-butyl ester, for example 2-bromoacetic acid-fe / t-butyl ester, in the Heat alkylated. After the reaction has ended, the heterogeneous base is filtered off and the desired product, the compound of the formula (VI), is crystallized by means of an antisolvent, for example water / ethanol. When 2-bromoacetic acid tert-butyl ester is used, formation of cyclization by-products occurs largely suppressed. These impurities and the resulting impurities in strontium ranelate are difficult to separate at the stage of strontium ranelate, so that the avoidance of these by-products represents a significant improvement of the production process.

In process step c) according to the invention, the compound (VI) isolated according to process step b) is converted into the diacid by means of an acid in an organic solvent, i. a compound of formula (VII).

In an alternative embodiment, the diacid may be further purified by recrystallization to subsequently obtain high purity strontium ranelate.

The process step c) according to the invention is generally carried out at temperatures of 20 ° C to 100 ° C, preferably at temperatures of 70 ° C to 80 ° C. The process step c) according to the invention is carried out in the presence of a strong organic acid. As such, all common strong organic acids come into question. These include, by way of example and by way of preference, arylsulfonic acids such as, for example, toluenesulfonic acid, alkylsulfonic acids such as methanesulfonic acid, haloalkylsulfonic acids such as trifluoromethanesulfonic acid, trichloroacetic acid or trifluoroacetic acid. Methane sulfonic acid or toluenesulfonic acid is preferably used in process step c).

Suitable diluents for carrying out process step c) are the organic solvents mentioned for process step b). Process step c) is preferably carried out in toluene.

The method step c) is described in particular as follows carried out. When carrying out the process step c) according to the invention, the compound of the formula (VI) is reacted in an organic solvent, for example toluene, by means of a strong organic acid, for example methanesulfonic acid, to give the corresponding diacid of the formula (VII) (eg compound 3) and after the end the reaction directly isolated.

Due to these reaction conditions, the formation of decarboxylation by-products is largely suppressed. Decarboxylation by-products are also difficult to separate from strontium ranelate and present a major hurdle to the production of high purity strontium ranelate, so avoiding these by-products is a significant improvement in the manufacturing process.

The process step d) according to the invention is generally carried out at temperatures of 10 ° C to 100 ° C, preferably at temperatures of 15 ° C to 25 ° C or at 70 to 90 ° C. In process step d), suitable strontium salts are strontium chloride, strontium bromide or strontium hydroxide. Strontium chloride is preferably used.

In process step d), the compound of the formula (VII) is reacted with an alkali metal hydroxide, such as lithium hydroxide, sodium hydroxide, potassium hydroxide; or sodium bicarbonate, preferably with dilute sodium hydroxide saponified to the tetrasodium salt and transferred by ion exchange with strontium salts directly into the desired strontium ranelate and crystallized. In an alternative embodiment of the process according to the invention, strontium ranelate of the formula (I) and its hydrates can be obtained by a process (variant B) comprising the process steps a), b) and c) described above, and after process step c) Process steps e) and f) comprises: e) reacting a compound of the formula (VII), in which Ri has the abovementioned meaning, with a base in an amount corresponding to 2 moles per mole of the compound of the formula (VII) a dialkali metal salt of the formula (VIII),

 (VIII) in which Ri has the meaning given above and A is Li, Na or K; and f) reacting a dialkali metal salt of formula (VIII) in which Ri and A have the meanings given above, with a base in an amount corresponding to 2.1 moles per mole of the compound of formula (VIII) and strontium hydroxide or strontium chloride to strontium ranelate of the formula (I) or its hydrates.

A is preferably Na. The compounds of formula (VIII) are new and also the subject of Invention. Preference is given to compounds of the formula (VIII) in which R 1 is ethyl and A is Na.

Variant B of the process according to the invention comprises the process steps a), b), c), e) and f) and is shown in FIG. 2 (Ri = ethyl (Et), R ₂ = C (CH ₃ ) ₃ ).

It can be described as extremely surprising that a significantly higher yield of strontium ranelate of the formula (I), namely about 71%, is obtained by the process according to the invention (variant B) than by processes known from the literature. In contrast, according to the process according to US 2004/0063972 A1 for stage 1 (cyclization) and stage 2 (alkylation) and WO 2007/020527 A2 for stages 3 and 4 (saponification with lithium hydroxide and ion exchange with strontium chloride) only an overall yield of strontium ranelate of Formula (I) of about 58%. According to the process described in US 2004/0063972 A1 with stages 1 (cyclization), stage 2 (alkylation) and stages 3 and 4 (saponification and ion exchange with strontium hydroxide), strontium ranelate of the formula (I) is obtained in an overall yield of about 64%. receive. Consequently, surprisingly, a significantly higher total yield is obtained by the process of variant B according to the invention.

In step e), the diacid (compound of formula (VII)) is treated under mild reaction conditions by reaction with 2 eq. Base, e.g. Sodium hydroxide, sodium bicarbonate, lithium hydroxide or potassium hydroxide, preferably sodium hydroxide, converted into the corresponding disodium salt of the formula (VIII). This reaction is surprisingly almost quantitative and leads to a further purification of the product.

The process step e) according to the invention is carried out in the presence of a suitable base. As such, all customary inorganic bases are suitable. By way of example and preferably Alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide or alkali metal bicarbonates such as sodium bicarbonate used. Sodium hydroxide is preferably used in process step e).

Process step e) is carried out under very mild conditions, e.g. with sodium hydroxide, carried out at room temperature.

In the subsequent process step f), the reaction of the dialkali metal salt of the formula (VIII) with a further 2.1 eq. Base, eg NaOH, and saline with a corresponding source of strontium, for example strontium hydroxide or strontium chloride, to give high-purity strontium ranelate. In a further embodiment of the process according to the invention, strontium ranelate of the formula (I) and its hydrates can be obtained by a process (variant C) comprising the process steps a) and b) described above, the process step g) described below and the process step d described above g) reacting a compound of the formula (VI) in which R 1 has the abovementioned meaning and R _{2 is} benzyl, with hydrogen in the presence of a heterogeneous catalyst and in the presence of a diluent to give a compound of the formula (VII), in which Ri and R _{2 have} the meanings given above.

It was surprisingly possible in process step g), starting from the dibenzyl ester of the formula (VI) in which R _{2 is} benzyl, by hydrogenolysis with a catalyst, in particular with Pd / C and hydrogen selectively to arrive at the compound of formula (VII) and thereby to avoid the side reaction of the cyclization and decarboxylation, so that high yields are obtained. Variant C of the process according to the invention comprises the process steps a), b), g) and d) and is shown in FIG. 3 (Ri = ethyl (Et), R ₂ = benzyl).

The process step g) is new and also the subject of the invention.

Suitable diluents in process step g) are alcohols such as methanol and ethanol or ethers such as tetrahydrofuran (with or without combination with water). Ethanol is particularly preferably used.

The process step g) is carried out in the presence of a heterogeneous catalyst. Suitable heterogeneous catalysts are, for example, palladium / C, palladium / aluminum oxide, palladium / barium carbonate, palladium / barium sulfate, palladium / strontium carbonate, platinum / C or platinum / aluminum oxide. In process step g) palladium on carbon is preferably used.

The process step g) according to the invention is carried out in particular as described below. When carrying out the process step g) according to the invention, the compound of the formula (VI) in which R _{2 is} benzyl is dissolved in an organic solvent and hydrogenated by means of a catalyst under hydrogen pressure to give the compound of the formula (VII). In summary, the process of variants A, B and C according to the invention makes it possible to produce high-purity strontium ranelate and its hydrates in high yields, with optional purification possibilities being available over various stages. Based on the Impurity profile of the intermediates, various combinations of intermediate isolations and purification steps can be applied to obtain optimum yield and purity. Examples

Example 1 (Variant A)

Process step a)

16.7 g of diethyl 3-oxoglutarate are dissolved in 20 ml of dimethylacetamide (DMA), treated with 4.95 g of malonodinitrile and the mixture is cooled to 10 ° C to 15 ° C. Subsequently, 7.6 g of triethylamine is slowly added. After completion of the reaction, the reaction mixture is heated to 20 ° C to 25 ° C and stirred for 30 min at this temperature. 2.41 g of sulfur are added and the mixture is heated to 75 ° C to 80 ° C. To

2 hours stirring time, another 0.24 g of sulfur are added and the mixture is further stirred at 75 ° C to 80 ° C until a reaction control shows complete conversion. 4.3 g of aqueous HCl (32% by weight) in 20 ml of water are slowly added. The mixture is cooled to 40 ° C to 50 ° C and a second portion of water (1 L / kg) was added. The resulting suspension is further cooled to 20 ° C to 25 ° C. The product is filtered off, washed with DMA and water and dried in vacuo. Yield: 18.8 g of compound 1. Process step b)

 4.3 g of compound 1 are dissolved in 10 g of acetone and 0.1 g of water. There are added 4.7 g of potassium carbonate and then with vigorous stirring 4.8 g of 2-bromoacetic acid tert-butyl ester. The mixture is for

Heated for 3 hours, filtered at room temperature and washed with 5 g of acetone. There are then added 15 g of ethanol and 9 g of water and cooled to 0 ° C. Thereafter, a further 19 g of water are slowly added dropwise. The product is filtered off with suction and washed with ethanol / water and dried in vacuo. Yield: 7.2 g of compound 2 process step c)

 1.28 g of compound 2 are dissolved in 10 g of toluene and mixed with 60 mg of methanesulfonic acid. The reaction mixture is heated to 70 ° C to 80 ° C and stirred for 3 hours. The precipitate is filtered off with suction in the heat at 50 ° C to 60 ° C and washed with toluene. The product is dried in vacuo.

Yield: 0.99 g of compound 3

Process step d)

260 mg of compound 3 are dissolved with 2.7 ml of 1N NaOH and stirred at room temperature for 3 hours. The undissolved residues are filtered. There are added dropwise 190 mg SrCl _{2 dissolved} in 1 ml of water and stirred at room temperature overnight. The precipitated residue is filtered off, washed several times with water and dried in vacuo overnight.

 Yield: 340 mg of strontium ranelate, purity> 99.8%. The structural formulas of compounds 1, 2 and 3 are shown in FIG. Example 2 (Variant C) Process Step g)

 480 mg of compound 4 are dissolved in 8 ml of ethanol, treated with 160 mg of palladium on carbon and hydrogenated under hydrogen pressure (1 bar) for 3 hours. The catalyst is filtered off with suction and the solvent is distilled off to a minimum. The residue is taken up in 5 ml of toluene and stirred for 2 hours at room temperature. The product is filtered off with suction and dried in vacuo.

Yield: 264 mg of compound 3.

The structural formulas of compounds 3 and 4 are shown in FIG.

Claims

 claims 1. Process for the preparation of strontium ranelate of the formula (I)

 (I) (Distrontium-5- [bis (carboxymethyl) amino] -2-carboxy-4-cyanothiophene-3-acetate) and its hydrates (variant A), which comprises the following steps: a) reaction of a compound of the formula (II),

in which Ri is CC ₄ -alkyl, with malononitrile of the formula (III) NCCN and sulfur in the presence of an organic diluent and in the presence of an organic base or heterogeneous inorganic base to a compound of the formula (IV),

 (IV) in which Ri has the meaning given above; b) reacting a compound of the formula (IV) in which R has the meaning indicated above with a compound of the formula (V) OR;  (V) in which X is bromine or chlorine and R _{2 is} Ci-C ₄ alkyl or benzyl, in the presence of a heterogeneous base, in the presence of an organic Solvent and in the presence of catalytic amounts of water to give a compound of formula (VI),

(VI) in which Ri and R _{2 have} the meanings given above; c) reaction of a compound of the formula (VI) in which R 1 has the abovementioned meaning and R _{2 is} C 1 -C ₄ -alkyl, with a strong organic acid, in the presence of an organic solvent to give a compound of the formula (VII)

in which Ri has the meaning given above; and d) reacting a compound of formula (VII) in which Ri is as defined above with an alkali metal hydroxide and a strontium salt in the presence of water Strontium ranelate of the formula (I) or its hydrates. 2. Method according to claim 1,  characterized,  in process step c) in the compounds of the formula (VI) Ri is ethyl and R _{2 is} tert-butyl. Method according to one of claims 1 or 2,  characterized,  that in process step c) an arylsulfonic acid, an alkylsulfonic acid or a haloalkylsulfonic acid is used as the strong organic acid. Method according to claim 3,  characterized,  that is used as a strong organic acid toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trichloroacetic acid or trifluoroacetic acid, in particular methanesulfonic acid. 5. Process for the preparation of strontium ranelate of the formula (I)

(Distrontium-5- [bis (carboxymethyl) amino] -2-carboxy-4-cyanothiophene-3-acetate) and its hydrates (variant B), the process steps a), b) and c) defined in claim 1, and after process step c) the process steps e) and f) comprises: e) reacting a compound of the formula (VII) in which Ri has the meaning given in claim 1 has, with a base in an amount corresponding to 2 moles per mole of the compound of the formula (VII), a dialkali metal salt of the formula (VIII),

 (VIII) in which Ri has the meaning given above and A is Li, Na or K; and f) reacting a dialkali metal salt of formula (VIII) in which Ri and A have the meanings given above, with a base in an amount corresponding to 2.1 moles per mole of the compound of formula (VIII) and strontium hydroxide or strontium chloride to strontium ranelate of the formula (I) or its hydrates. 6. Process for the preparation of strontium ranelate of the formula (I)

 (I) (Distrontium-5- [bis (carboxymethyl) amino] -2-carboxy-4-cyanthiophene-3-acetate) and its hydrates (variant C), which comprise the process steps a) and b) as defined in claim 1, process step g) : g) reacting a compound of the formula (VI) in which Ri is C 1 -C ₄ -alkyl and R _{2 is} benzyl with hydrogen in the presence of a heterogeneous catalyst in the presence of a diluent to give a compound of the formula (VII), in which Ri has the meaning given above, and the process step d) defined in claim 1. 7. compound of the formula (VI)

in which ethyl and R _{2 is} tert-butyl. Compound of the formula (VI)

(VI) in which Ri is ethyl and R _{2 is} benzyl. 9. compound of formula VII),

(VII) in which Ri is C 1 -C ₄ -alkyl. 10. compound of the formula (VIII)

(VIII) in which Ri is C 1 -C ₄ -alkyl and A is Li, Na or K. 11. Process for the preparation of a compound of the formula (IV)

(IV) in which Ri is C 1 -C ₄ -alkyl, by reacting a compound of the formula (II),

 (II) in which Ri has the abovementioned meaning, with malononitrile of the formula (III) N c CN (III)  and sulfur in dimethylacetamide, in the presence of an organic base. 12. Process for the preparation of a compound of formula (VII)

 (VII) in which R 1 is C 1 -C ₄ -alkyl, by reaction of a compound of the formula (VI)

(VI) in which Ri has the abovementioned meaning and is in particular ethyl, and R _{2 is} C 1 -C ₄ -alkyl, in particular ter-butyl, with a strong organic acid, in the presence of an organic solvent. 13. The method according to claim 12,  characterized,  that is used as a strong organic acid toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, trichloroacetic acid or trifluoroacetic acid, in particular methanesulfonic acid. 14. Process for the preparation of a compound of the formula (VII)

 (VII) in which ^ is C 1 -C ₄ -alkyl, in particular ethyl, by reaction of a compound of the formula (VI)

(VI) in which Ri has the abovementioned meaning and is in particular ethyl, and R _{2 is} benzyl,  with hydrogen in the presence of a heterogeneous catalyst, especially palladium on carbon, in the presence of a diluent. 15. The method according to any one of claims 1 to 4,  characterized,  that in process step b) as a catalytic amount of water 0.1-5 eq. Water is used.