AN IMPROVED PROCESS FOR THE PREPARATION OF STRONTIUM

RANELATE HYDRATES

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of pure strontium ranelate hydrates (Ia-c) by using the intermediates, amino dimethyl ester of formula-II and tetramethylester of formula-III, which are prepared by novel methods.

Ia- Strontium ranelate octahydrate: n=8
Ib- Strontium ranelate tetrahydrate: n=4
Ic- Strontium ranelate monohydrate: n=l

BACKGROUND OF THE INVENTION

Osteoporosis is a systemic skeletal disorder characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility. The clinical consequences of osteoporosis are vertebral and peripheral fractures. Postmenopausal osteoporosis affects women after menopause and results from an accelerated rate of bone loss mainly due to oestrogen deficiency. Thus, there is an increase in bone turnover, resulting in a decrease in bone mass and bone mineral density. Strontium ranelate, an anti-osteoporotic agent which helps in both increasing bone formation and reducing bone resorption, resulting in a rebalance of bone turnover in favour of bone formation. Therefore strontium ranelate is considered as an important medicament in bone disorder diseases and it is marketed as protelos.

Strontium ranelate is a distrontium salt of ranelic acid and the chemical name is: distrontium 5-[bis(carboxymethyl)amino]-3-carboxymethyl-4-cyano-2-thiophene carboxylic acid, represented as formula-I.

DESCRIPTION OF THE PRIOR ART

EP 0415850 provides the processes for the preparation bivalent salts of ranelic acid, including strontium ranelate, and their therapeutic use. In this patent, preparation of strontium ranelate hydrates like octahydrate, heptahydrate and tetrahydrate are reported but purity of the products are not mentioned.

US Patent No. 7105683 provides preparation of amino diester of formula-II, an intermediate for the preparation of strontium ranelate, by reacting 1,3-acetone carboxylic acid dimethyl ester, malononitrile and sulfur in methanol in presence of a base - morpholine.

US Patent No.7091364 provides process for the preparation of tetraester, methyl 5-[bis(2-methoxy-2-oxoethyl)amino]-4-cyano-3-(2-methoxy-2-oxoethyl)-2-thiophenecarboxylate of formul-III, which is another intermediate of strontium ranelate. The process involves reaction of methyl 5-amino-4-cyano-3-(2-methoxy-2-oxoethyl)-2-thiophenecarboxylate of formula-II with methyl or ethyl bromoacetate in an organic solvent, in presence of potassium carbonate and a catalyst C8-C10type quaternary ammonium salt.

US Patent No.7214805 provides the processes for the preparation of intermediates of formula-II and formula-Ill and also strontium ranelate octahydrate. In this patent, the intermediates, amino diester of formula-II and tetra ester of formula-HI are prepared by adopting the methods described in US patents 7105683 and US 7091364 respectively, whereas strontium ranelate octahydrate is prepared by heating tetraester of formula-Ill with strontium hydroxide in water medium.

PCT Publication No. WO 2010/021000 also provides the processes for the preparation of intermediates of formula-II and formula-Ill and also strontium ranelate octahydrate. In this patent preparation methods of intermediates as well as strontium ranelate octahydrate are described and the details are as follows: amino diester of formula-II is prepared by reacting 1,3-acetone dicarboxylic acid dimethyl ester, malononitrile and sulfur in methanol medium by using a different base imidazole in place of morpholine. Tetra ester of formula-Ill is prepared by reacting amino diester of formula-II with ethyl bromoacetate in a mixture of organic solvents like acetonitrile and dimethyl sulfoxide or acetone and dimethyl sulfoxide in presence of potassium iodide and potassium carbonate. Strontium ranelate octahydrate is prepared via lithium salt by reacting tetra ester of formula-Ill with aqueous lithium hydroxide in tetrahydrofuran medium followed by addition of strontium chloride. However the methodology is having certain disadvantages like usage of mixture of solvents in preparation tetraester of formula-Ill and class-II solvent, tetrahydrofuran, in active pharmaceutical ingredient (API) formation stage.

Though above mentioned processes are disclosed in the prior art to obtain strontium ranelate, still an improved methodology can be developed for the preparation of quality API in respect of high chemical purity and with less impurity profile. In the present invention an improved, economical and industrial scalable processes for the preparation of pure strontium ranelate hydrates have been described.

SUMMARY OF THE INVENTION

One aspect of the present invention provides a novel process for the preparation of amino diester of formula-II by using an alternative, cheap and commercially available base- triethyl amine.

Another aspect of the present invention provides an economical process for the preparation of tetra ester of formula-III by using a cheap and commercially available catalyst- cetrimide.

Another important aspect of the present invention provides a process to obtain a high quality active pharmaceutical ingredient (API), strontium ranelate octahydrate represented by the formula-la, tetrahydrate represented by the formula-lb and monohydrate represented by the formula- Ic. The API obtained by the present process is excellent in chemical purity, more than 99.80% by HPLC, and with less or negligible impurities. Thus the present invention provides a process to obtain a very pure API which is matching all the quality attributes as per pharmaceutical and ICH guidelines.

Another important aspect of the present, strontium ranelate octahydrate has water content of about 21.5 wt % to about 23.5 wt %, strontium ranelate tetrahydrate has a water content of about 11.0 wt % to about 13.0 wt % and strontium ranelate monohydrate has a water content of about 3.0 wt % to of about 4.5 wt %. There are known methods in the art to determine the water content of a chemical substance such as for example the Karl-Fischer (KF) titration method, the loss on drying (LOD) method and thermogravimetric analysis (TGA) method. For the present invention loss on drying (LOD) analysis method is adopted for the determination of water content.

The chemical reactions involved in the present process for preparation of strontium ranelate octahydrate are shown in synthetic scheme.

SYNTHETIC SCHEME

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an improved and a cost effective industrial process for the preparation of very pure active pharmaceutical ingredient-strontium ranelate octahydrate (la) and other hydrates like strontium ranelate tetrahydrate (lb) and strontium ranelate monohydrate (Ic).

In an embodiment, the present invention provides strontium ranelate octahydrate and other hydrates obtained by the described process are having purity greater than 99.50% and more preferably greater than 99.80% as measured by HPLC.

In another embodiment, the present invention provides a process to obtain strontium ranelate octahydrate and other hydrates having very less process related impurities, the individual impurities lower than 0.2 % and more preferably lower than 0.1% , and total impurities lower than 0.5% and more preferably lower than 0.2% as measured by HPLC.

In another embodiment, the present invention provides a process to obtain strontium ranelate octahydrate and other hydrates having very negligible residual solvent impurities or organic volatile impurities which are lower than ICH norms.

One aspect of the present invention provides an improved process for the preparation of amino diester of formula-II, which comprises,

a) Preparation of a mixture of dimethyl 3-oxoglutarate of formula-IV, malononitrile of formula-V and triethylamine of formula-VI, in an organic solvent.

b) heating the reaction mass obtained in step a) to form triethylamine complex of formula-VII in situ.

c) heating the reaction mass obtained in step a) or b) with sulfur and

d) isolating of amino diester of formula-II.

One embodiment of the present invention, wherein step a) of providing a mixture comprising of dimethyl 3-oxoglutarate, malononitrile and triethylamine in an organic solvent to form a compound of complex of methyl 3-(dicyanomethylene)-5-hydroxy-5-methoxy-4-pentenoate with triethylamine of formula-VII.

Another embodiment of the present invention, wherein step a) of heating a mixture of dimethyl 3-oxoglutarate, malononitrile and triethylamine in an organic solvent, about 65-70°C to form a complex of methyl 3-(dicyanomethylene)-5-hydroxy-5-methoxy-4-pentenoate with triethylamine of formula-VII.

Yet another embodiment of the present invention wherein the organic solvent is used in reaction of dimethyl 3-oxoglutarate, malononitrile and triethylamine is selected from a C1-C4 alcohol, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ketones such as acetone, methyl isopropyl ketone, methyl isobutyl ketone and mixtures thereof, preferably methanol.

Yet another embodiment of the present invention further involves compound of complex of methyl 3-(dicyanomethylene)-5-hydroxy-5-methoxy-4-pentenoate with triethylamine formed in situ is reacted with sulfur without isolating the triethylamine complex to provide an amino diester of formula-II.

Another aspect of the present invention provides process for the preparation of the tetra methyl ester of formula-Ill, which comprises,

a) reacting of methyl 5-amino-4-cyano-3-(2-methoxy-2-oxoethyl)-2-thiophenecarboxylate of formula-II with methyl bromoacetate of formula-VIII in an organic solvent in presence of an inorganic base and a catalyst-cetrimide,

b) isolating compound of formula-III.

One embodiment of the present invention, wherein step a) of reacting with
compound of methyl 5-amino-4-cyano-3-(2-methoxy-2-oxoethyl)-2-
thiophenecarboxylate and methyl bromoacetate is carried in presence of inorganic base and organic solvent using a catalyst-cetrimide, a C17 quaternary ammonium salt and the reaction is carried out at reflux temperature, about 80-82°C followed by isolation of a compound of formula-III,

Another embodiment of the present invention wherein the organic solvent used in reacting compound of methyl 5-amino-4-cyano-3-(2-methoxy-2-oxoethyl)-2-thiophenecarboxylate and methyl bromoacetate is selected from a C1-C4 alcohol, such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ketones such as acetone, methyl isopropyl ketone, methyl isobutyl ketone and the nitriles such as acetonitrile and the mixtures thereof, preferably acetonitrile.

Yet another embodiment of the present invention wherein the inorganic base used in reacting compound of methyl 5-amino-4-cyano-3-(2-methoxy-2-oxoethyl)-2-thiophenecarboxylate and methyl bromoacetate is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, preferably potassium carbonate.

Another aspect of present invention provides process for the preparation of strontium ranelate, octahydrate of formula-Ia, which comprises:

a) hydrolyzing tetraester of formula-III with strontium hydroxide in an
aqueous medium,

b) heating the reaction mass obtained in step a) about 100 -102°C,

c) isolating strontium ranelate and,

d) heating in an aqueous isopropyl alcohol to obtain strontium ranelate octahydrate of formula-la,

Yet another embodiment of the present invention provides process for the preparation of strontium ranelate tetrahydrate of formula-lb, which comprises:

a) addition of strontium ranelate octahydrate of formula-la into the isopropanol,
b) heating the reaction mass obtained in step a) about 80 -85°C,

c) isolating strontium ranelate tetrahydrate of formula-lb,

Yet another embodiment of the present invention provides process for the preparation of strontium ranelate monohydrate of formula-Ic, which comprises;

a) charging of strontium ranelate octahydrate or tetrahydrate in to a rotocone vacuum dryer,

b) heating the product preferably at 95-100°C under vacuum,

c) till loss on drying of product attained to 3.0 to 4.5%,

d) cooling the product to 25-30°C, and

e) collecting the strontium ranelate monohydrate of formula-Ic.

EXAMPLES

Example-1: Process for the preparation of methyl 5-amino-4-cyano-3-(2-methoxy-2-oxoethyl)-2-thiophenecarboxylate of formula-II:

Dimethyl 3-oxoglutarate (100 g), methanol (140 ml), malononitrile (37.93 g) were charged in to a round bottom flask and the reaction mixture was cooled to 10°C. Triethylamine (57.99 g) was added slowly to the reaction mixture at 10°C and temperature of the reaction mixture was raised and maintained at 65-70°C for 2 hours. The reaction mass was cooled to 25-30°C. Sulfur (18.39 g) was charged and again heated at 65-70°C for 2 hours. The reaction mass was cooled to 45-50°C and water (700 ml) was added and further cooled to 10°C. The product was filtered, crystallized from methanol and dried to give pure title compound. Yield: 98 g Purity: 99.50%

Example-2: Process for the preparation of methyl 5-[bis(2-methoxy-2- oxoethyl) aminol-4-cyano-3-(2-methoxy-2-oxoethyl)-2-thiophenecarboxylate of formula-III;

Acetonitrile (700 ml), potassium carbonate (95.13 g), compound of formula-II (100 g), cetrimide (4.0 g) and methyl bromoacetate (132.24 g) were charged in to a round bottom flask and heated at 80-82°C for 4 hours. Later reaction mass was cooled to 25-30°C and filtered the inorganic salts, the filtrate was concentrated to give crude product, which was crystallized from methanol, filtered and dried to furnish pure title compound. Yield: 110 g Purity: 99.88%

Example-3: Process for the preparation of strontium ranelate octahydrate of formula-Ia:
Strontium hydroxide (153.50 g), DM water (3500 ml) and the compound of formula-III were charged in to a round bottom flask and heated at 100°C-102°C for 12 hours. Reaction mass was cooled and filtered the product. The product was taken in to aqueous isopropanol, heated for 4 hrs, filtered and dried to obtain pure title product

Yield: 146 g
Purity: 99.92%
Loss on drying by TGA: 22.5%

Example-4: Process for the preparation of strontium ranelate tetrahydrate of formula-Ib:
Strontium ranelate octahydrate (100 g) and isopropanol (600 ml) were charged in to a round bottom flask and heated at 80-85°C for 2 hours. Cooled the reaction mass to room
temperature, filtered the material and dried at 60-65°C for 4 hours to give title compound of formula lb.

Yield: 81.5 g
Purity: 99.87%
Loss on drying by TGA: 12.2%
Example-5: Process for the preparation of strontium ranelate monohydrate of formula-Ic:

Strontium ranelate octahydrate (150 g) was charged into a rotocone vacuum dryer and
heated at 95°C-100°C for 25 hours under vacuum. Then dryer is cooled to room temperature and material is collected.

Yield: 115 g
Purity: 99.88%
Loss on drying by TGA: 4.41%

CLAIMS:

1. A process for the preparation of compound of formula-II, which comprises,

a) providing a mixture comprising compound of dimethyl 3-oxoglutarate of formula-IV and malononitrile of formula-V in presence of triethylamine of formula-VI in an organic solvent,

b) heating the reaction mixture of claim la) for the formation of complex of methyl 3-(dicyanomethylene)-5-hydroxy-5-methoxy-4-pentenoate with triethylamine of formula-VII in situ,

c) treating the complex claim 1a) or 1b) with sulfur and

d) isolating compound of formula-II (amino diester).

2. A process for the preparation of the compound of formula-Ill, which comprises,

a) reacting compound of methyl 5-amino-4-cyano-3-(2-methoxy-2-oxoethyl)-2-thiophenecarboxylate of formula-II, of claim 1d), with a compound of methyl bromoacetate of formula-VIII, and

b) reaction is carried out in an organic solvent-acetonitrile in the presence of cetrimide and an inorganic base-potassium carbonate.

c) isolating compound of formula-III.

3. An enolate intermediate of compound of complex of methyl 3-(dicyanomethylene)-5-hydroxy-5-methoxy-4-pentenoate with triethylamine of formula-VII in situ,

4. A process for the preparation of strontium ranelate octahydrate of formula-Ia, which comprises:

a) providing a mixture, comprising of dimethyl 3-oxoglutarate of formula-IV
and malononitrile of formula-V in presence of triethylamine of formula-VI and organic solvent to form a compound, complex of methyl 3-(dicyanomethylene)-5-hydroxy-5-methoxy-4-pentenoate with triethylamine of formula-VII,

b) treating compound of complex of methyl 3-(dicyanomethylene)-5-hydroxy-5-methoxy-4-pentenoate with triethylamine of formula-VII obtained in step 4a) with sulfur to provide a compound of methyl 5-amino-4-cyano-3-(2-methoxy-2-oxoethyl)-2-thiophenecarboxylate of formula-II.

c) reacting the compound of methyl 5-amino-4-cyano-3-(2-methoxy-2-oxoethyl)-2-thiophenecarboxylate of formula-II obtained in step 4b) with compound of methyl bromoacetate of formula-VIII, in presence of cetrimide and an organic solvent-acetonitrile to provide a compound of methyl 5-[bis(2-methoxy-2-oxoethyl)amino]-4-cyano-3-(2-methoxy-2-oxoethyl)-2-thiophenecarboxylate of formula-III(tetramethyl ester).

d) hydrolyzing a compound of methyl 5-[bis(2-methoxy-2-oxoethyl)amino]-4-cyano-
3-(2-methoxy-2-oxoethyl)-2-thiophenecarboxylate of formula-III with strontium
hydroxide in water medium followed by heating in aqueous isopropyl alcohol to give
strontium ranelate of formula-Ia.

5) A process for the preparation of strontium ranelate tetrahydrate of formula-Ib, which comprises:

a) addition of strontium ranelate octahydrate of formula-la obtained in claim 4d) into an organic solvent-isopropyl alcohol,

b) heating the reaction mass at about 80 -85°C,

c) isolating strontium ranelate tetrahydrate of formula-lb.

6) A process for the preparation of strontium ranelate monohydrate of formula-Ic, which comprises:

a) charging strontium ranelate octahydrate or tetrahydrate in to a rotocone
vacuum dryer,

b) heating the product at 95-100°C under vacuum, till loss on drying of product attained to 3.0 to 4.5%,

c) cooling the product to 25-30°C, and collecting the strontium ranelate monohydrate of formula-Ic.

7. The process according to claims 1 to 6, involves without isolation of compound of complex of with triethylamine of formula-VII.