FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Strontium ranelate of formula I, more particularly the present invention relates to an economically viable and industrially advantageous process for the preparation of Strontium ranelate of formula I, intermediate or hydrates thereof.

BACKGROUND OF THE INVENTION Strontium ranelate of formula I, a strontium (II) salt of ranelic acid, is used in the treatment for osteoporosis. It is promoted as a "dual action bone agent" in the sense that it both increases deposition of new bone osteoblasts and reduces the resorption of bone by osteoclasts. Strontium ranelate is chemically known as distrontium salt of 2-[N,N-di(carboxymethyl)amino]-3-cyano-4- carboxymethyl thiophene-5-carboxylic acid or distrontium 5-[bis(2-oxido-2-oxoethyl)amino]-4- cyano-3-(2-oxido-2-oxoethyl)thiophene-2-carboxylate. Commercially, strontium ranelate is available under the trade name Protelos ^® in Europe.

Formula I

Ranelic acid and its divalent metal salts were first disclosed in US 5,128,367, wherein three methods for the preparation of strontium ranelate are described. The first method involves hydrolysis of tetraester of ranelic acid in ethanol using aqueous sodium hydroxide at reflux for approximately 4 hours to form the sodium salt of ranelic acid intermediate. The sodium salt is further treated with sulphonic resin to obtain crude ranelic acid which is recrystallized from ethyl ether followed by treatment with tetrahydrofuran or acetone to obtain pure ranelic acid with 70% yield. Further the acid is treated with strontium hydroxide octahydrate to obtain heptahydrate of strontium ranelate, which when allowed to crystallize for 24 to 48 hours under reduced pressure (10 mm) at 55°C, can be converted into tetrahydrate

In the second method, the tetraester of ranelic acid is refluxed in ethanol and aqueous sodium hydroxide approximately 4 hours to obtain sodium salt of ranelic acid. Further, solvent is removed by distillation which is then treated with ethanol to obtain precipitate of sodium salt which is filtered and dried. Further, the sodium salt of ranelic acid is dissolved in water and treated with aqueous strontium chloride to form octahydrate of strontium ranelate. The third method involves treatment of the tetraester of ranelic acid with strontium hydroxide in ethanol and water, followed by distillation of ethanol and further, the aqueous solution is heated to 100°C, filtered hot and the residue is washed with water to obtain octahydrate of strontium ranelate. The above described methods involve long reaction time and distillation of solvents at high temperature which leads to higher impurity formation and increased production cost. EP-B-1 403 265 describes a process for the preparation of tetraester compounds of ranelic acid, which involves reaction of methyl bromoacetate with 5-amino-3-(carboxymethyl)-4-cyano-2- thiophenecarboxylic acid in an solvent in the presence of C ₈ -C ₁₀ type quaternary ammonium compounds at reflux temperature to obtain methyl 5-[bis(methoxy-2-oxoethyl)amino]-4-cyano- 3-(2-methoxy-2-oxoethyl)-2-thiophenecarboxylate. The reaction time is approximately 5 hours. However, the major drawback of the process is use of hazardous reagents and expensive catalyst. Methyl/ethyl bromoacetate is a highly hazardous due to its strong lachrymatory properties and also commercially expensive. C ₈ -C] ₀ type quaternary ammonium compounds, e.g. Aliquat 336 ^® , Adogen 464 ^® etc, are expensive for commercial use. However the process of EP-B- 1403265 involves long reaction time about 5 hours which gives 85% yield and >98% chemical purity.

CN 101139337 discloses the preparation of strontium ranelate by reacting ethyl 5-amino-4- cyano-3-(2-ethoxy-2-oxoethyl)-2-thiophenecarboxylate with ethyl chloroacetate in presence of trimethylbenzyl ammonium chloride to obtain the corresponding tetra-ester, which is converted to strontium ranelate. This process requires long reaction time of approximately 12 hours. Purity and impurity level of the product have not been reported. The process described in CN-A- 101139337 also involves very long reaction time, about 12 hours which gives 80% yield and the patent application is silent about purity of the product.

The above mentioned methods for the preparation of strontium ranelate or hydrates thereof are tedious, expensive and dangerous in operation; therefore, there is a need to develop an improved process suitable for industrial production of strontium ranelate or hydrates thereof and its intermediates with optimum yield and purity.

SUMMARY OF THE INVENTION

It is, therefore, an object of the present invention to provide an improved process for the preparation of Strontium ranelate, which overcomes the deficiencies of the prior art processes and results to a cost effective industrial production without scarifying the yield and quality of the product.

Another object of the present invention is to provide an improved method for the preparation of Strontium ranelate or hydrates thereof by selecting the appropriate reactants, catalysts, solvent systems and conditions used during the organic reactions, so that the purity and yield of the reaction are increased and the presence of any contaminants and formed by-products is minimized.

A further object of the present invention is to provide an economically viable, industrially feasible and environmentally benign process for the preparation of strontium ranelate of formula I or hydrates thereof in high purity.

An additional goal of the present invention is to provide an improved process for the preparation of intermediate useful in the manufacture of strontium ranelate of formula I or hydrates thereof.

In accordance with the above objects of the present invention, a process for the preparation of compound of formula IV, is provided,

Formula IV

wherein R and R' are the same or different, each represent a linear or branched or alicyclic C C ₆ alkyl group, and

said process comprises a step of alkylating compound of formula III

Formula III

with a chloroacetate compound of formula CICH2COOR', wherein R' has the same meaning as defined above in the presence of a base, an iodide source as a reaction rate enhancer in suitable solvent.

In another aspect, the present invention provides a process for the preparation of above mentioned compound of formula III comprising a step of reacting compound of formula II, Formula II wherein R has the same meaning as defined above, with malononitrile and sulphur in the presence of organic base.

In another aspect, the present invention provides a process for the preparation of strontium ranelate of formula I from compound of formula IV.

In yet another aspect, the present invention provides an improved process for the preparation of strontium ranelate of formula I or hydrates thereof, comprising a step of alkylating compound of formula III with a chloroacetate compound in the presence of a base, an iodide source as a reaction rate enhancer in suitable solvent to obtain compound of formula IV.

Preferred embodiments of the present invention are set out in dependent claims 2 to 13.

Other objects and advantages of the present invention will become apparent to those skilled in the art in view of the following detailed description.

BRIEF DESCRIPTION OF THE DRAWING

FIG.1 shows an X-ray powder diffraction pattern of strontium ranelate obtained by process of the present invention wherein the moisture content is about 19.0 to 21.4% w/w.

FIG.2 shows an X-ray powder diffraction pattern of strontium ranelate obtained by process of the present invention wherein the moisture content is about 21.5 to 22.9% w/w.

DETAILED DESCRIPTION OF THE INVENTION

Throughout the present invention, unless otherwise stated, the term "ambient temperature" means 20-45°C, preferably 25-35°C. The term "reflux temperature" means boiling temperature of the solvent used. The present invention describes a 3 -stage process for the preparation of strontium ranelate of formula I or hydrates thereof.

In the stage-I, a compound of formula II, wherein R represent a linear or branched or alicyclic d-C ₆ alkyl group, is reacted with malononitnle and subsequently with sulphur in the presence of an organic base and optionally in suitable solvent at about ambient temperature to about reflux temperature for a few minutes to a few hours, preferably at a temperature of about 30-70°C for about 1 hour.

Formula II

Suitable organic base is selected from N,N-diethylethanemine, N-(l-methylethyl)-2- propanamine, l,4-diazabicyclo[2.2.2]octane, triethylamine, tributylamine, diisopropylamine, and the like, preferably triethylamine. The suitable solvent includes alcohols such as methanol, ethanol, n-propanol, isopropanol and the like or mixtures thereof, preferably ethanol.

Without isolation and purifying the product obtained from the reaction of the compound of formula II with malononitrile, sulphur is directly added to the reaction mass to facilitate cyclization. The mixture is heated at about reflux temperature for about 1-5 hours, preferably about 2-3 hours, more preferably till the completion of the reaction. The completion of reaction is monitored by any suitable technique such as thin layer chromatography (TLC) or high performance liquid chromatography (HPLC) or gas chromatography. After completion of the reaction water is added to precipitate the compound of formula III, wherein R has the same meaning as defined above.

Formula III

In stage-II, the compound of formula III obtained from process of stage-I, is preceded for alkylation with a chloroacetate compound of formula ClCH ₂ COOR', wherein R' represents a linear or branched or alicyclic C C ₆ alkyl group, in the presence of base, an iodide source as a reaction rate enhancer in suitable solvent to obtain compound of formula IV. Most of the prior art processes employ an ester of bromoacetate in this stage of preparation. Bromoacetate compounds are highly hazardous compounds. They are well-known as lachrymator and create serious irritations upon inhalation and skin absorption. Industrial processes using bromoacetate compounds are disadvantageous not only because their market prices are high but also because of it posts harmful risk in operation. Therefore, substituting chloroacetate compounds in the place of bromoacetate compounds is meaningful and advantageous.

The base used in this stage may be inorganic base or organic base. Said inorganic base is selected from alkali and alkaline earth metal carbonates like potassium carbonate, sodium carbonate, lithium carbonate, magnesium carbonate, calcium carbonate alkali and alkaline earth metal hydroxide like sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide or mixtures thereof. Said organic base is selected from triethylamine, tripropylamine, tributylamine, diisopropylamine, diisopropylethylamine and the like or mixtures thereof. Conventionally, a phase transfer catalyst may also be used to enhance the reaction time. Said phase transfer catalyst is selected from C ₃ -C ₅ tetra alkyl ammonium chloride such as tetra propyl ammonium chloride, tetra butyl ammonium chloride, tetra pentyl ammonium chloride and the like or C ₃ -C ₅ tetra alkyl ammonium bromide such as tetra propyl ammonium bromide, tetra butyl ammonium bromide, tetra pentyl ammonium bromide and the like preferably tetra butyl ammonium bromide. According to one aspect of the present invention, the alkylation reaction of compound of formula III with a chloroacetate compound is being carried out in the presence of an iodide source. The inventors of present invention have observed that the rate of reaction is significantly enhanced or accelerated by the use of iodide source and the product thus obtained are in increased purity higher yield as compared to methods available in the prior art. The iodide source includes alkali metal iodide such as potassium iodide or sodium iodide or tetrabutyl ammonium iodide. The reaction is carried out at temperature at about ambient temperature to about reflux temperature of solvent. The reaction time may vary from about 30 minutes to about 3 hours.

Suitable solvent for the above reaction include ketones such as acetone, methylethyl ketone, methyl isobutyl ketone, methyl propyl ketone, methyl isopropyl ketone, cyclohexanone, nitriles such as acetonitrile, propionitrile and the like or mixtures thereof or their mixtures with water.

In one of the preferred embodiments, the compound of formula III is reacted with ethyl chloroacetate in the presence of potassium carbonate as base, potassium iodine as an iodide source and optionally tetrabutyl ammonium bromide as a phase transfer catalyst, in acetone as suitable solvent. The reaction is carried out preferably at reflux temperature for about 1-1.5 hours. The completion of reaction is monitored by any suitable technique such as thin layer chromatography (TLC). After completion of the reaction the compound of formula IV is isolated by conventional techniques known such as acid-base treatment, extraction with solvent, column chromatography and the like.

In stage-Ill, the compound of formula IV, wherein R and R' each independently represents a linear or branched or alicyclic Ci-C ₆ alkyl group, by process described in stage-II, is converted into the strontium ranelate compound of formula I or hydrates thereof by the techniques known in the prior art or as per process described in the present invention.

Formula IV

In one of the preferred embodiment, compound of formula IV is converted into strontium ranelate or hydrate thereof by reaction of compound of formula IV with strontium hydroxide in suitable solvent. The solvent include ketone, such as acetone, methylethyl ketone, methyl isobutyl ketone, or alcohols, such as methanol, ethanol, isopropanol, n-propanol, n-butanol and the like, or water or mixtures thereof, preferably water. The reaction is carried out at ambient temperature to reflux temperature for about 1-5 hours, preferably till the completion of the reaction. The completion of reaction is monitored by any suitable technique such as thin layer chromatography (TLC) or high performance liquid chromatography (HPLC) or gas chromatography. After completion of the reaction the compound of formula I is isolated by conventional techniques given in the prior art such as acid-base treatment, extraction with solvent, column chromatography and the like.

In another preferred embodiment, compound of formula IV is converted into strontium ranelate or hydrate thereof by reaction of compound of formula IV with base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, preferably sodium hydroxide. The salt thus obtained may be isolated or proceed to the next step without isolation. The obtained salt is treated with strontium salt selected from strontium chloride, strontium bromide, strontium nitrate, strontium sulphate, strontium acetate and the like, preferably strontium nitrate in suitable solvent. The solvent include ethers such as diethyl ether, isopropyl ether, tetrahydrofuran and the like or ketone such as acetone, methylethyl ketone, methyl isobutyl ketone or alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol and the like or water or mixtures thereof, preferably tetrahydrofuran. The reaction is carried out at ambient temperature to reflux temperature for about 1-5 hours, preferably till the completion of the reaction. The completion of reaction is monitored by any suitable technique such as thin layer chromatography (TLC) or high performance liquid chromatography (HPLC) or gas chromatography (GC). After completion of the reaction the compound of formula I is isolated by conventional techniques given in the prior art such as acid-base treatment, extraction with solvent, column chromatography and the like.

The process for the preparation of Strontium ranelate according to the present invention will be described in detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limit to the scope of the reaction in any manner. EXAMPLES

Example 1 : Preparation of ethyl 5-amino-4-cvano-3-(2-ethoxy-2-oxoethyl)-2-thiophene carboxylate compound of formula HI Triethylamine (25 g) was added to a solution of malononitrile (16.33 g) and diethyl-3- oxogutarate (50 g) in ethanol (75 ml) at ambient temperature. The reaction mixture was stirred at 40-45°C for 1 hour. Sulphur (7.9 g) was added into the reaction mass and was heated to reflux till the completion of reaction. The reaction mass was cooled at ambient temperature and added water (400 ml) slowly. Stirred the reaction mixture for 1 hour and filtered the product, washed with water (200 ml) and dry the product at 40-50°C. Yield 82%.

Example 2: Preparation ethyl- 5-fbis (2-ethoxy-2-oxoethyn amino ^" l-4-cvano-3-(2-ethoxy-2- oxoethyl)-2-thiophenecarboxylate compound of formula IV Example 2(a): Ethyl 5-amino-4-cyano-3-(2-ethoxy-2-oxoethyl)-2-thiophenecarboxyla te (10 g) was added in acetone (70 ml) and water (3 ml) at ambient temperature followed by the addition of potassium carbonate (10.7 g), potassium iodide (1 g), tetra butyl ammonium bromide (1 g) and ethyl chloroacetate (11.8 g) and reaction mass was heated to reflux for 60-90 minute. The reaction mass was cooled to ambient temperature. The reaction mass was filtered and washed with acetone (30 ml). The filtrate was concentrated under vacuum below 50°C. Ethanol (30 ml) was added to the concentrated mass and heated the reaction mixture till clear solution is obtained. Thereafter reaction mixture was cooled, filtered the product and washed with ethanol (30 ml). Product was dried at 40-50°C. Yield 90%. Example 2(b): Ethyl 5-amino-4-cyano-3-(2-ethoxy-2-oxoethyl)-2-thiophene carboxylate (10 g) was added in acetone (70 ml) and water (3 ml) at ambient temperature followed by the addition of potassium carbonate (10.7 g), potassium iodide (2 g) and ethyl chloroacetate (11.8 g) and the reaction mass was heated to reflux for 3 hours. The reaction mass was cooled to ambient temperature. The reaction mass was filtered and washed with acetone (30 ml). The filtrate was concentrated under vacuum below 50°C. Ethanol (30 ml) was added to the concentrated mass and heated the reaction mixture till clear solution was obtained. Thereafter the reaction mixture was cooled. The product was filtered and washed with ethanol (30 ml), dried the product at 40- 50°C. Yield 90%.

Example 2(c): Ethyl 5-amino-4-cyano-3-(2-ethoxy-2-oxoethyl)-2-thiophene carboxylate (10 g) was added in acetone (70 ml) and water (3 ml) at ambient temperature followed by the addition of potassium carbonate (10.7 g), tetrabutyl ammonium iodide (2 g) and ethylchloro acetate (11.8 g) and reaction mass was heated to reflux for 3 hour. The reaction mass was cooled to ambient temperature. The reaction mass was filtered and washed with acetone (30 ml). The filtrate was concentrated under vacuum below 50°C. Ethanol (30 ml) was added to the concentrated mass and heated the reaction mixture till clear solution was obtained. Thereafter reaction mixture was cooled. The product was filtered and washed with ethanol (30 ml) and dried the product at 40- 50°C. Yield 91%.

Example 3: Preparation of Strontium Ranelate compound of formula I

Example 3(a): To a stirred solution of strontium hydroxide (5.84 g) and water (50 ml) followed by the addition of ethyl- 5-[bis(2-ethoxy-2-oxoethyl) amino]-4-cyano-3-(2-ethoxy-2-oxoethyl)- 2-thiophenecarboxylate (5 g). The reaction mass was heated to reflux and continue refluxing for a minimum of 5 hours. Then reaction mixture was filtered and washed the wet cake with water. The obtained product distrontium salt of ranelic acid was dried under fan at 25-35°C optionally in oven for 1.5-2.5 hours (moisture content: 21.5 -22.9% w/w); further drying under fan at 25- 35°C optionally in oven for additional 1-2 hours (moisture content: 19.0-21.4%), Yield approximately 85%, HPLC purity >99%.

Example 3(b): To a stirred mixture of ethyl- 5-[bis (2-ethoxy-2-oxoethyl) amino]-4-cyano-3-(2- ethoxy-2-oxoethyl)-2-thiophenecarboxylate (50 g) and tetrahydrofuran (75 ml), the aqueous solution of NaOH (20 g NaOH in 200 ml Water) was added. The reaction mixture was stirred for 4-6 hour at about 20-35°C. The aqueous solution of Sr(N0 ₃ ) ₂ (51.2 g) was added and stirred for about 20 hour. The product was filtered and washed with water. The obtained product distrontium salt of ranelic acid was dried under fan at 25-35°C optionally in oven for 1.5-2.5 hours (moisture content: 21.5-22.9%w/w); further drying under fan at 25-35°C optionally in oven for additional 1-2 hours (moisture content: 19.0-21.4%), Yield approximately 87%, HPLC purity >99.5%.

Example 3(c): To a stirred mixture of ethyl- 5 -[bis (2-ethoxy-2-oxoethyl) amino]-4-cyano-3-(2- ethoxy-2-oxoethyl)-2-thiophenecarboxylate (50 g) and tetrahydrofuran (75 ml), the aqueous solution of NaOH (20 g NaOH in 200 ml water) was added. The reaction mixture was stirred for 4-6 hour at about 20-35°C. The aqueous solution of SrS0 ₄ (67.7 g) was added and stirred for about 20 hour. The product was filtered and washed with water. The obtained product distrontium salt of ranelic acid was dried under fan at 25-35°C optionally in oven for 1.5-2.5 hours (moisture content: 21.5-22.9% w/w); further drying under fan at 25-35°C optionally in oven for additional 1-2 hours (moisture content: 19.0-21.4%), Yield approximately 88%, HPLC purity >99.5%. The alkylation process of present invention results in that the present invention has superior purity and higher yield within shorter reaction time. The present invention involves less reaction time about 1 -3 hours for the completion of the reaction and gives increased yield about 90% and higher HPLC purity >99%.

Moisture/Water Content of Strontium Ranelate:

It was observed that the X-ray powder diffraction pattern of strontium ranelate depends upon the moisture/water content as determined by the Karl Fischer method.

Strontium ranelate wherein the moisture content is about 19.0 to 21.4% w/w gives characteristic X-ray powder diffraction having significant reflections expressed as 2Θ ±0.2 values and % of intensity as given in below table.

2Θ±0.2 values % of intensity

7.6 22.0

9.0 40.6

11.4 11.6

12.1 9.4

13.1 21.5

14.2 5.3

14.8 16.6

16.0 25.9

16.8 17.0

17.4 20.2

18.0 12.1

19.1 14.0

19.9 15.0

23.1 26.9

24.0 100

25.9 50.4

28.1 47.5

29.6 31.3

30.1 56.3

32.1 17.6

33.3 36.2

34.6 15.9

35.6 22.8

36.3 24.1

38.3 40.4 Strontium ranelate wherein the moisture content is about 21.5 to 22.9% w/w gives characteristic X-ray powder diffraction having significant reflections expressed as 2Θ ±0.2 values and % of intensity as given in below table.

While the present invention has been described with respect to the particular embodiments, it will be apparent to those skilled in the art that various changes and modifications may be made in the invention without departing from the scope thereof, as defined in the appended claims.