FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patent Rules, 2006
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. TITLE OF THE INVENTION: An improved process for the preparation of substantially pure strontium ranelate of formula I and hydrates thereof of formula IA"
2. Applicant

(a) NAME: Arch Pharmalabs Limited
(b) NATIONALITY: Indian
(c) ADDRESS: 541-A, Arch House, Marol-Maroshi Road, Marol,
Andheri (East), Mumbai -400 059, India
PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

TITLE: An improved process for the preparation of substantially pure strontium raneiate of formula I and hydrates thereof of formula IA.

FIELD OF TECHNOLOGY: The present invention relates to an improved, commercially viable and industrially advantageous process for the preparation of substantially pure strontium raneiate of formula I and hydrates thereof of formula IA. In particular, the process disclosed herein proposes an improved process over the closest prior art that improves the impurity profile of the product thereby meeting the current pharmaceutical requirements. The process described herein comprises the use of compounds of formulae II, III as key intermediates. Intermediate of formula III comprises the reaction of compound of formula II and compound of formula VII in presence of a base.

BACKGROUND OF THE INVENTION:
Strontium ranelate, distrontium salt of 5-[bis(carboxymethyl)amino]-3-carboxymethyl-4-cyano-2-thiophenecarboxylic acid represented by formula I, has very valuable pharmacological and therapeutic properties, especially pronounced anti-osteoporotic properties, making this compound useful for the treatment of bone diseases. Osteoporosis is a systemic skeletal disorder characterized by low bone mass and micro architectural deterioration of bone tissues, leading to enhanced bone fragility. The clinical consequences of osteoporosis are vertebral and peropheral fractures. Postmenopausal osteoporosis affect women after menopause and results into an accelerated rate of bone loss mainly due to oestrogen deficiency thereby decreasing bone mass and bone mineral density. Strontium ranelate is an anti osteoporotic agent which helps in both increasing bone formation and reducing bone resorption resulting in

a rebalance of bone turnover in favor of bone formation, therefore, making it an important medicament.
Strontium ranelate and its first synthesis was disclosed in EP 0415850 and US 5128367 (hereinafter referred to as the '367 patent). Strontium ranelate is sold under the brand name PROTELOS™ for the treatment of postmenopausal osteoporosis to reduce the risk of vertebral and hip fractures. It is administered as granules for oral suspension containing 2 g of strontium ranelate. It is important to note that the dose of strontium ranelate that is given to a patient is 2 g/day and hence it is absolutely necessary to consider impurity profile a necessary parameter before it is used for the pharmaceutical composition.
US7105683 discloses the process for the preparation of amino diester of formula II, an intermediate for the preparation of strontium ranelate comprising the reaction of 1,3-acetone carboxylic acid dimethyl ester, malononitrile and sulphur in presence of a base morpholine as depicted herein below:

US7091364 discloses a process for the preparation of tetraester of formula III, which is another intermediate of strontium ranelate. The

process comprises the reaction of amino diester of formula II with methyl or ethyl bromoacetate in an organic solvent in the presence of potassium carbonate and a quaternary ammonium salt as phase transfer catalyst as depicted herein below:

Bull. Soc. Chim. France 1975, pages 1786-1792 discloses a process for
the preparation of tetraethyl ester of 2-[N,N-di(carboxymethyl)amino]-3-
cyano-4- carboxymethylthiophene-5-carboxylic acid comprising reacting
diethyl 3-oxoglutarate with malononitrile and sulphur in ethanol in the
presence of morpholine or diethyl amine to produce ethyl 5-amino-3-
ethoxycarbonylmethyl-4-cyano-2-thiophenecarboxylate, which is then
reacted with ethyl bromoacetate in the presence of potassium carbonate
in acetone to produce the tetraethyl ester of 2-[N,N-
di(carboxymethyl)amino]-3-cyano-4- carboxymethylthiophene-5-
carboxylic acid as depicted herein below:


US 5128367 disclose three methods for the synthesis of divalent metal
salts of 2-[N,N-di(carboxymethyl)amino]-3-cyano-4-
carboxymethylthiophene-5-carboxylic acid, for example, strontium ranelate.
According to a first synthetic process as disclosed therein, strontium
ranelate is prepared by heating the tetraethyl ester of 2-[N,N-
di(carboxymethyl)amino]-3- cyano-4-carboxymethylthiophene-5-
carboxylic acid at reflux in an aqueous alcoholic medium in the presence of sodium hydroxide solution, followed by acidification to give 2-[N,N-di(carboxymethyl)amino]-3-cyano-4-carboxymethyIthiophene-5-carboxylic acid, which is then reacted with strontium hydro xide.8H20 in an aqueous medium to produce octahydrate of strontium ranelate. The octahydrate of strontium ranelate is then converted into heptahydrate by drying the octahydrate of strontium ranelate under a stream of dry air, which is further converted into corresponding tetrahydrate by drying the heptahydrate under reduced pressure (10 mm) at 55°C.

According to a second synthetic process, strontium ranelate is prepared by heating the tetraethyl ester of 2-[N;N-di(carboxymethyl)amino]-3-cyano-4- carboxymethylthiophene-5-carboxylic acid at reflux in a

mixture of sodium hydroxide solution and ethanol to produce a reaction mass, followed by distillation under vacuum in a water bath to remove the ethanol and the majority of the water. The resulting oil is precipitated with ethanol and the sodium salt obtained is filtered and then dried in vacuum at 50°C. The resulting tetra-sodium salt is dissolved in water, the filtered solution is added to a solution of strontium chloride in water and the resulting mixture is rapidly homogenized and then left to stand for 24 hours. The process is depicted herein below. The distrontium salt formed, in the form of octahydrate, is separated by filtration.

According to a third synthetic process, strontium ranelate is prepared by
heating a mixture of tetraethyl ester of 2-[N,N-
di(carboxymethyl)amino]-3-cyano-4- carboxymethylthiophene-5-
carboxylic acid, strontium hydroxide, water and ethanol at reflux for 1 hour and followed by distillation of ethanol. The resulting aqueous solution is heated to 100°C, followed by filtration. The resulting residue is washed with water and the octahydrate of strontium ranelate obtained is separated by filtration. The process is depicted in the scheme given herein below.


'367 does not indicate the purity profile of the product obtained by any of the process described therein. Processes disclosed therein in '367 comprises use of sodium hydroxide as additional base and additional operational step, use of multiple reaction solvent system for the preparation of salt of the tetra ester. The inventor of the present invention has observed that when alcohol is used as a solvent it suppresses the solubility of strontium hydroxide thereby resulting into less purity of the final API.
WO2010/021000 (hereinafter refered as '000) discloses the process for the preparation of intermediates of formulae II and III and also strontium ranelate octahydrate. The process for the preparation of amino diester of formula II comprises the reaction of 1,3-acetone dicarboxylic acid dimethyl ester with malononitrile and sulphur in methanol using a different base imidazole replacing morpholine.


Tetraalkylester of formula III is prepared by reaction of amino diester of formula II with ethylbromo acetate in a mixture of organic solvents like acetonitrile and dimethyl sulphoxide or acetone and dimethyl sulphoxide in the presence of potassium iodide and potassium carbonate as depicted herein below:

Strontium ranelate octahydrate is prepared by the process comprising the reaction of tetra ester of formula III with lithium hydroxide using tetrahydrofuran as a solvent, followed by the addition of strontium chloride.
Example 5 of' 000 describes hydrolysis of tetra ester of the formula III using aqueous lithium hydroxide as a base and tetrahydrofuran as a co-solvent and takes 8 hrs for the completion yielding ranelic acid. This is followed by the formation of strontium salt comprising the reaction of ranelic acid so produced with strontium chloride that takes about 20 hrs for the completion.
However, the disadvantages associated with ' 000 is the use of class II solvent like tetrahydrofuran at the stage of formation of active pharmaceutical agent itself and a very large duration for the product to

come out, use of lithium hydroxide as additional base required for the hydrolysis of the tetra ester.
WO2011/124992 discloses the process for the preparation of strontium ranelate comprising preparations, isolation and recrystalisation of the various intermediates viz. compounds of formulae II, III and sodium ranelate obtained at the various stages by solvent/antisolvent concept. Sodium ranelate is then further converted into strontium ranelate using strontium chloride. The drawback associated with said patent application is multiple operational steps, thereby making unsuitable at the plant level. The said patent also discloses various impurities of strontium ranelate. The said patent discloses recrystalisation of the crude compound of formula II obtained using a first solvent medium comprising a solvent and an anti-solvent, wherein the solvent is an ester solvent and the anti-solvent is an aliphatic hydrocarbon, to produce pure compound of formula II. The example 1 of the said prior art discloses the acetate solvent in the ratio of 1:2(w/v) and anti solvent in the range of(l:3w/v).
However, inventors of the present invention have found that there exists a close relationship in the moisture content of the crude material of formula II and volume of acetate solvent required to dissolve the crude completely, a necessary condition for recrystalization. As per their findings it has been found that if the moisture content of crude material of formula II is in the range of 7-10% and it enables it to dissolve in two

times volume of acetate solvent (1:2 w/v) as otherwise it requires a larger volume of acetate solvent and consequently thereby consumes a larger volume of antisolvent.
WO2011/124992 discloses a general mode of purification to reduce all the disclosed impurities comprising isolation and purification of all the intermediates. It does not indicate any probable cause of impurity formation. Inventors of the present invention have observed that the compounds represented by formulae impurity A and impurity G are the most prominent impurities which generally remains trapped in the final product strontium ranelate. Impurity G is the product obtained by partial or incomplete hydrolysis of the tetra ester of formula III. Out of four ester groups, one ester group remains unhydrolysed as shown herein below as impurity G. International application WO2011/124992 discloses the impurity G as a novel compound formed as an impurity but neither gives any indication for a process to have the control its formation nor proposes any mode to minimize the said impurity.

The impurity A is a known impurity and gets formed due to use the degraded keto dicarboxylate of formula IV. It has been observed that if the keto dicarboxylate of formula IV wherein R is methyl group on

degradation produces (of formula IV). This degradation product of formula (IV) reacts with sulphur and malononitrile in alcoholic solvent to generate the impurity of formula A as depicted herein below:

In the instant invention formation of impurity A is either eliminated or minimized by using the substantially pure keto dicarboxylate of formula IV, (wherein R is ethyl) free from the degraded product of formula IV during the preparation of compound of formula II.
Substantially pure keto dicarboxylate mean to use the said compound substantially free from the degradation product with purity of at least
98%.

This type of degradation is common with compound of formula IV wherein R is methyl or any other alkyl group, and that will be generating the corresponding impurity similar to that of impurity A.
The closest prior art to the present invention is US7214805 which discloses the process for the preparation of strontium ranelate as shown below comprising refluxing tetra ester of formula III with strontium hydroxide at least for 5 hours in water as medium as depicted herein below:

However, the said product obtained based on the process disclosed therein is only 98% chemically pure as given in example 3 without specifying the impurity profile. Inventors of the present invention have worked on the same parameters of the reaction as disclosed in the said prior art and observed that the heating of the reaction mass containing compound of formula IT and strontium hydroxide at reflux temperature at-least for five hours results into 97% pure product (RT: 20.67) along with the formation of about 2% impurity of formula G(RT:37.73) indicating that high temperature for prolonged time is not a favorable factor for the said reaction. The analytical results of the product obtained

based on the process disclosed therein in the said prior art are depicted herein below in HPLC chromatograph in figure I:

FIGURE I
Another closest prior art is WO2011/124992, which discloses the formation of impurity G but does not teach or indicate how to control or minimize the formation of impurity G during the preparation of strontium ranelate.
Inventors of the instant invention disclose herein an improved process which provide solution to the shortcomings of the prior art process comprising short duration of reaction time at lower temperature for complete hydrolysis of compound of formula III to eliminate or

minimize the formation of impurity G as evident from the chromatograph as depicted herein below in figure II:

FIGURE II
It is a known fact that synthetic compounds can contain extraneous compounds or impurities formed during the synthesis or degradation. The impurities can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. Generally, impurities in an active pharmaceutical ingredient (API) arise from degradation of the API itself, or unreacted reactants or byproducts formed during the preparation of the API. Impurities in strontium ranelate or any active pharmaceutical ingredient (API) are undesirable and might be harmful.

Regulatory authorities worldwide require that drug manufacturers isolate, identify and characterize the impurities in their products. Furthermore, it is required to control the levels of these impurities in the final drug compound obtained by the manufacturing process and to ensure that the known or unknown impurity or impurities are present in the lowest possible levels as specified in the drug specifications.
The product mixture of a chemical reaction is rarely a single compound with sufficient purity to comply with pharmaceutical standards. Side products and byproducts of the reaction and adjunct reagents used in the reaction will, in most cases, also be present in the product mixture. Purity standards are set with the intention of ensuring that an API is as free of impurities as possible, and, thus, are as safe as possible for clinical use. The United States Food and Drug Administration guidelines recommend that the amounts of some impurities are limited to less than 0.1 percent.
There are evolving and more rigorous requirements demanded for drug manufacturers and with the prevailing disadvantages present with the prior art, there is a need for an improved process for the preparation of strontium ranelate and its intermediates, which circumvent the formation of process related impurities, while ensuring a target strontium ranelate product with optimum yield and purity.
Moreover it is important here to note that the molecule strontium ranelate is a non pharmacopeial product and its dose is 2 g/day, therefore it becomes

absolutely necessary to know the impurity profile. As per CPMP/ICH/2737/99 guidelines if the daily dose of the drug is 2g then the reporting threshold is 0.05%, identification threshold is 0.10% or 1.0 mg (which 'ever is lower) per day intake is permissible, qualification threshold is 0.15% or 1.0 mg (which ever is lower) per day intake permissible. Therefore it is clearly understood from the above data that individual impurity intake for a dose of 2 g/day should not exceed 1.0 mg.
Various thresholds used in the para is defined herein below:
Reporting Threshold: A limit above (>) which an impurity should be reported.
Identification Threshold: A limit above (>) which an impurity should be identified.
Qualification Threshold: A limit above (>) which an impurity should be qualified.
In other words, for the molecule tike strontium ranelate which is administered as 2 g/day, the individual impurity intake from this much quantity should not exceed 1.0 mg (0.05%). As per the market specification for strontium ranelate' individual impurity should be less than 0.05% and total impurity should be less than 0.5%.
Inventors of the present invention disclose herein an improved process providing solution to the shortcomings of prior art US7214805 and WO2011/124992 comprising heating reaction mass containing compound of formula III, strontium hydroxide and about 65 volumes of

water w.r.t. compound of formula III at temperature below reflux temperature for less than 5 hours to obtain substantially pure strontium ranealate having about 99.8% purity in about 78-80% yield minimizing or eliminating the formation of impurity of formula G which is generally formed by partial hydrolysis of the tetra ester of formula III.
TECHNICAL PROBLEM RELATED TO STRONTIUM RANELATE:
1. Major' problem while working on strontium ranelate is its solubility in any of the solvent.
2. Limited solubility of strontium hydroxide in water
3. Difficulties in the separation and removal of the impurities from the reaction mass containing strontium ranelate.
4. Trapping of the impurity G in strontium ranelate is due to solubility difference, impurity G precipitates earlier than the API molecule.
5. Formation of the impurity A is due to the degradation product of formula IV
6. High dose of strontium ranelate to be given per day, therefore it needs special attention for the impurities associated with the molecule.

7. Limit of the individual impurity is not to exceed lmg/2g strontium ranelate.
TECHNICAL SOLUTION PROVIDED BY THE INVENTION:
1. Elimination or minimizing the formation of impurities of Formulae G during the synthesis of strontium ranelate.
2. Elimination or minimizing the formation of impurity A or other impurity similar to that of A during the preparation of strontium ranelate by using substantially pure keto dicarboxylate of formula IV.
3. Substantially pure Strontium ranelate complying with the regulatory requirements.
4. The instant invention discloses a process comprising the use of optimized volume of water that will facilitate the hydrolysis to completion (keeping solubility concept of strontium hydroxide as well as strontium ranelate in the view), at lower temperature than reflux of water for shorter duration and also the molar equivalent of strontium hydroxide used for the hydrolysis; thereby eliminating or minimizing the formation of undesirable side product characterized as impurity G.
Following Table-I will reveal the optimization of all the process parameters to get substantially pure finished product as per the current pharmacopeia! requirement:

Table- II reveals the effect of process temperature and time to get substantially pure finished product as per the current pharmacopeial requirement:
TABLE-I

Molar ratio of Sr(OH)2 w.r.t. tetra ester of formula III Volume of water
w.r.t. tetra ester of
formula III % of Impurity G formed Purity %
3 equivalent 65 volume 0.09% 99.75%
3.2 equivalent 50 volume 0.672% 99.1%
3.2 equivalent 65 volume Less than 0.05% 99.8%
TABLE-II

Temperature for hydrolysis Time % of Impurity G formed Purity %
100°C (reflux) 5 hrs 1.79% 97.76%
70 °C lhr 0.04% 99.75%
OBJECTS OF THE INVENTION:
First aspect of the instant invention is an improved, efficient, commercially viable and environment friendly process for the

preparation of substantially pure strontium ranelate chemically known as distrontium salt of 5-[bis(carboxymethyl)amino]-3-carboxymethyl-4-cyano-2- thiophenecarboxylic acid, of formula 1 substantially free of impurities. Advantageously, the process comprises shorter reaction time and produces the product with higher purity and yields.
Second aspect of the instant invention is to provide strontium ranelate comprising impurity-G in an amount of about 0.01 area-percent to about 0.05 area-percent; and wherein the strontium ranelate has a purity of about 99.5% to about 99.99% as measured by HPLC.
Third aspect of the invention is to provide a process for the preparation of strontium ranelate at a temperature less than reflux temperature of water used as solvent system that eliminates or minimizes the formation of impurities of Formula G resulting in the formation of substantially pure product compared to product obtained at reflux temperature for longer duration as disclosed in US7214805.
Fourth aspect of the invention is to provide a process for the preparation of strontium ranelate that is completed in less time than 5 hrs when compared to at-least 5 hrs as disclosed in US7214805.
Fifth aspect of the invention is to provide a process for the preparation of strontium ranelate of formula I and hydrates thereof;
comprising the steps of:


With malononitrile of formula V;
a) contacting substantially pure ketonic tricarboxylic acid ester of formula IV ;

in a solvent selected from aliphatic alcohols , in the presence of a base selected from morpholine, imidazole, pyridine, N,N'-dimethyl aniline and the like to yield the compound of formula VI;

b) compound of formula VI obtained in step a is then contacted with sulphur to yield the compound of formula II;


c) purifiying the compound of formula II containing 7-11% moisture content using a first solvent medium comprising a solvent and an anti-solvent, wherein the solvent is an ester and anti-solvent is an aliphatic hydrocarbon, to produce pure compound of formula II;
d) compound of formula II obtained in step c is then contacted with compound of formula VII in an organic solvent in the presence of a base, optionally in presence of phase transfer catalyst to yield the compound of formula III;

e) purifying the crude compound of formula III obtained in step d using a second solvent medium comprising a solvent and an anti-solvent, wherein the solvent is an amide solvent and anti-solvent is an alcohol solvent, to produce pure tetraethyl ester compound of formula III;
f) compound of formula III obtained in step e is contacted with strontium hydroxide in water in such a volume so that strontium hydroxide gets dissolved and compound of formula III undergoes complete hydrolysis,

at a temperature below reflux temperature of water used as solvent and heating the reaction mass for less than 5 hrs to yield after drying substantially pure compound of formula I and hydrates thereof.

Sixth aspect of the invention is to provide a process for the preparation of strontium ranelate of formula I and hydrates thereof comprising the steps of;
a) contacting the compound of formula III with strontium hydroxide

at temperature below reflux temperature of water, for less than 5 hours, the precipitate obtained is filtered off to obtain powder which after drying gives substantially pure compound of formula I and hydrates thereof.


Advantage of the process under the instant invention is that it comprises the hydrolysis of tetra ester of formula III at temperature lower than the reflux temperature of water used as a solvent and for shorter duration compared to the process conditions disclosed in the prior art reference US7214805 making the process industrially viable and economical and resulting in a substantially pure strontium ranelate of formula I and hydrates thereof in higher yield with total impurities less than about 0.5%.
SUMMARY OF THE INVENTION:
The instant process relates to an improved process for the preparation of substantially pure strontium ranelate and hydrates thereof comprising contacting substantially pure amino dimethyl ester of formula II with substituted halo ester of formula VII and optimizing the reaction parameters over the prior art thereby improving the impurity profile and yield. The process under the instant invention comprises the hydrolysis of tetra ester of formula III at temperature below the reflux temperature of water used as a solvent for shorter duration contrary to the reaction parameters disclosed in the prior art thereby eliminating or minimizing the formation of undesired byproducts like impurity G yielding substantially pure strontium ranelate of formula I and hydrates thereof.
The entire schematic representation is depicted herein below:


The word contacting used hereinabove and herein below means reacting, heating, stirring, mixing, refluxing and the like.
The process for the preparation of strontium ranelate of formula I and hydrates thereof disclosed herein is summarized as follow;
with malononitrile of formula V;
a substantially pure ketonic dicarboxylic acid ester of formula IV is contacted


in a solvent in presence of a base selected from morpholine, imidazole, pyridine, N,N'-dimethyl aniline and the like to obtain the compound of formula VI;


The compound of formula VI is contacted with sulphur to yield the compound of formula II; purifying the compound of formula II containing 7-11% moisture content using a first solvent medium comprising a solvent and an anti-solvent;

The compound of formula II is then contacted with compound of formula VII

in an organic solvent, in presence of base, optionally in presence of a phase transfer catalyst to yield the compound of formula III; purifying the crude compound of formula III obtained using a second solvent medium comprising a solvent and an anti-solvent and the said compound of formula III is then contacted with strontium hydroxide in water in


such a volume so that strontium hydroxide used gets dissolved and compound of formula III undergoes complete hydrolysis, at a temperature below reflux temperature of water used as solvent for less than 5 hrs to yield after drying substantially pure compound of formula I and hydrates thereof.

DETAILED DISCREPTION OF THE INVENTION:
Disclosed herein is an efficient, economical and industrially viable process for the preparation of substantially pure strontium ranelate of formula (1) and hydrates thereof substantially free from impurities. The disclosure of the present invention has been described herein below in detail in non limiting embodiments.
In a general embodiment of the instant invention disclosed herein is a process for the preparation of strontium ranelate of formula I and hydrates thereof wherein the process comprises the steps of:

a) contacting substantially pure ketonic dicarboxylic acid ester of formula IV with malononitrile of formula V in a solvent in the presence of a base to yield the compound of formula VI;
b) optionally isolated compound of formula VI obtained in step a is then contacted with sulphur at a suitable temperature to yield the compound of formula II;
c) purifying the compound of formula II containing 7-11% moisture content using a first solvent medium comprising a solvent and an anti-solvent;
d) compound of formula II obtained in step c is contacted
with the compound of formula VII in an organic solvent in
the presence of a base optionally in the presence of phase
transfer catalyst to yield the compound of formula III;
e) purifying the tetra alkyl compound of formula III using second solvent medium comprising a solvent and an anti solvent;
f) tetra alkyl ester of the formula III obtained in step e is contacting with suitable quantity of strontium hydroxide (depending upon its assay) in water as a solvent in such a volume so that strontium hydroxide gets dissolved completely and sufficient to cause the complete hydrolysis

of tetra ester of formula III thereby eliminating or minimizing the formation of impurity G at a temperature below reflux temperature of water for a time less than 5 hrs resulting into the precipitation of substantially pure strontium ranelate of formula I and its hydrate having purity about 99.8% in about 76-80% yield with total impurities less than about 0.5 %;
g) the product in step d is filtered off and dried under vacuum.
The entire schematic representation of the invention is depicted herein below:

Ketonic dicarboxylic acid ester of formula IV used in the embodiment is selected from C1-C6 linear or branched alkyl groups esters preferably methyl or ethyl ester.
Solvent used in the process for the preparation of compound of formula VI/II is any organic solvent that will have no adverse effect on the reaction preferably C1-C6 alcoholic solvent selected from the group comprising methanol, ethanol, n-propanol, isopropanol and the like. Preferably solvent is methanol.

The base used in the process for the preparation of compound of formula VI/1I is any organic base. Preferably organic base is selected frommorpholine, imidazole, pyridine, N,N'-dimethyI aniline and the like More preferably organic base is morpholine. Temperature for the above embodiment is suitable temperature that will have no negative effect on the reaction.
The compound of formula VII is C1-C6 alkyl halosubstituted ester preferably bromo ester.
Solvent used in the process for the preparation of compound of formula III is any organic solvent that will have no adverse effect on the reaction preferably C1-C6 alcoholic solvent, ketonic solvent, acetate solvent selected from the group comprising methanol, ethanol, n-propanol, isopropanol, acetone, methyl ethyl ketone, ethyl acetate and the like, preferably acetone.
Base used in the process for the preparation of compound of formula II is preferably inorganic base selected from the group comprising alkali metal carbonate, alkali metal bicarbonate preferably potassium carbonate.
Phase transfer catalyst used in the process for the preparation of compound of formula II is any quaternary ammonium salts or any other catalyst used for the same purpose.

The first solvent medium used for the purification of compound of formula II is ester solvent selected from the group comprising C1-C4 alkyl based ester solvent preferably ethyl acetate and anti-solvent is aliphatic acyclic or cyclic C3-C6, hydrocarbon preferably cyclohexane.
The compound of formula III is C1-C6 alkyl tetra ester preferably methyl or ethyl tetra ester.
The second solvent medium used for the purification of compound of formula III comprises an alcohol solvent preferably isopropanol and anti-solvent is an etheral solvent preferably methyl tert butyl ether.
The quantity of strontium hydroxide used is in the range of about 2.5 to about 4 equivalent moles depending on its assay profile preferably about 3.2 equivalents to that of tetra ester of formula III.
Volume of water used for the hydrolysis of compound of formula III to obtain compound of formula I/I A is such that strontium hydroxide that is used gets completely dissolved and hydrolysis of tetra ester of formula III undergoes to the completion avoiding formation of undesired byproduct like impurity G, preferably in the range of about 50-80 volume to that of compound of formula 111 more preferably about 65 volumes.
Temperature for the hydrolysis is such that strontium hydroxide that is used gets completely dissolved and hydrolysis of tetra ester of formula III undergoes to the completion avoiding formation of undesired by-

product like impurity G. Preferably temperature is the range of about 50 to about 80°C preferably about 70 °C.
Duration of the hydrolysis is such that hydrolysis of tetra ester of formula III undergoes to the completion leaving no scope for the other impurities to be generated. Preferably duration is about 0.5 to about less than 5 hrs more preferably about 1 hour.
In a specific embodiment of the instant invention disclosed herein is a process comprising the steps:
a) contacting substantially pure dimethyl-1,3-
acetonedicarboxylate with malononitrile in methanol in the
presence of morpholine at room temperature to yield the
compound of formula VI wherein R is methyl group;
b) contacting compound of Formula VI obtained in step a with
sulphur and the said reaction mixture is heated at reflux
yielding compound of formula II wherein R is methyl;
c) purifying the compound of formula II containing 7-11%
moisture content using ethyl acetate solvent and cyclohexane
as an anti-solvent;
d) compound of formula II obtained in step c is contacted with
bromoethylacetate and K2C03 in acetone at room temperature
to give a compound of formula III wherein R' is ethyl and R is
methyl group;

e) purifying the compound of formula III using isopropanol as a solvent and methyl tert butyl ether as an antisolvent;
f) the compound of formula III obtained in step e is then contacted with aqueous solution of strontium hydroxide at room temperature to obtain a suspension; the said suspension is then heated to about 70°C for about 1.0 hr resulting into the formation of substantially pure strontium ranelate of formula I.
In another specific embodiment of the instant invention disclosed herein is a process for the preparation of substantially pure strontium ranelate of formula I comprising contacting compound of formula III with an aqueous solution of strontium hydroxide comprising about 65 times water compared to quantity of compound of formula III at room temperature to obtain a suspension. The said suspension is then heated at about 70°C for about 1.0 hr resulting into the formation of substantially pure strontium ranelate of formula 1.
The invention is further illustrated by the following examples which are not intended to limit the invention in any way.
Example 1: Preparation of compound of formula II; wherein R is methyl group:


To a well stirred solution of 98 % pure dimethyl-1,3-acetonedicarboxylate (100.0 g,0.574 mol.) and malononitrile (37.9 g, 0.574 mol) in methanol was added morpholine (50 .0 g, 0.574 mol. ) at room temperature and stirred for 1 h at 45°C. Sulphur (18.4 g, 0.574 mol) was then added in one lot to the reaction mixture and heated at reflux for 12-14 h. After completion of the reaction methanol was distilled out and reaction mass was cooled to room temperature. To this reaction mass was added water (1200 mL) and further cooled to 10-15°C for complete precipitation. The precipitated product was filtered, washed with cold waterand dried under vacuum at 45-50°C to obtain crude stage-I (95 % yield, with 96 % HPLC purity).The crude product so obtained is further purified from ethyl acetate and cyclohexane to yield purified compound of formula II. (75 % yield and 99 % purity).
Example 2: Preparation of compound of formula III wherein R is methyl and R1 is ethyl group

To a well stirred suspension of stage-I (110 g, 0.43 mol) and K2CO3 (149.6 g, 1.08 mol) in acetone (1.1L) was added bromoethylacetate (180.8 g, 1.08 mol) at room temperature. The reaction mixture was heated at reflux for 10-12 h. The reaction mass was filtered and acetone

is distilled under reduced pressure to obtain a semisolid mass to which was added isopropyl alcohol (220 mL) and heated to 70°C for 30 min. The reaction mixture was gradually cooled to room temperature to this water (330 mL) was added for complete precipitation. The reaction mass was filtered and washed with chilled isopropyl alcohol followed by water to yield wet cake which on drying gave crude Stage -II (90% yield with 96% HPLC purity.) The crude product so obtained is further purified by IPA and MTBE as solvent system to yield purified compound of formula III. (88 % yield and 99 % purity).
Example 3: Preparation of strontium ranelate of formula I and its hydrates thereof of formula IA:

To solution of Strontium hydroxide (prepared by dissolving Sr(OH)2.8H20, 20.0 g, 75.0 mmol in 650 mL of water) was added (5-[bis(2-amino-2-oxoethyl)amino]-4-cyano-2-(methoxycarbonyl)-3-thiopheneacetic acid methyl ester (II) (10 g, 23.5 mmol) at room

temperature. The suspension was heated at 70°C for 1.0 hr and then allowed to cool gradually at 25°C. The reaction mass was filtered off and washed with water and dried further to obtain white strontium ranelate of formula IA (80% yield with purity 99.8 %).

CLAIMS:
We claim:
1. A process for the preparation of substantially pure strontium ranelate of formula I and its hydrate thereof of formula IA

comprising the steps:

with malononitrile of formula V;
a) contacting substantially pure ketonic dicarboxylic acid ester of formula IV;

in a solvent, in the presence of a base to yield the compound of formula VI;


b) compound of formula VI obtained in step a is contacted with sulphur to yield the compound of formula II;

c) optionally purifying the compound of formula II containing about 7 to
about 12% moisture content using a first solvent medium comprising a
solvent and an anti-solvent;
d) compound of Formula II obtained in step c is contacted with
compound of formula VII in an organic solvent in the presence of base,
optionally in presence of phase transfer catalyst to yield the compound
of formula III;



e) optionally purifying the crude compound of formula III obtained in step d using a second solvent medium comprising a solvent and an anti-solvent to produce pure tetra alkyl ester compound of formula III;
f) contacting compound of formula III obtained in step e with strontium hydroxide in water at temperature below reflux temperature of water for not more than 5 hours, the precipitate obtained is filtered and dried to yield a compound of formula I and hydrates thereof of formula I A.
2. A process for the preparation of substantially pure strontium ranelate of formula I and hydrates thereof of formula IA

comprising contacting tetra alkyl compound of formula III with strontium hydroxide in water at temperature below reflux temperature of water, for not more than 5 hours, the precipitate obtained is

filtered and dried to obtain compound of formula I and hydrates thereof of formula I A.

3. The process of claim 1 step a wherein base used for the preparation of compound of formula VI is selected from group comprising morpholine, imidazole, pyridine, N, N'-dimefhyl aniline and mixture thereof.
4. The process of claim 1 step a wherein solvent for the process for the preparation of compound of formula VI/II is selected from group comprising C1-C6 alcoholic solvent comprising methanol, ethanol, n-propanol, isopropanol and mixture thereof.
5. The process of claim 4 wherein solvent is methanol.
6. The process of claim 1 step b wherein base used for the preparation of compound of formula II is selected from the group comprising alkali metal carbonate and alkali metal bicarbonate.
7. The process of claim 6 wherein base is potassium carbonate.
8. The process of claim I step b wherein phase transfer catalyst used for the process for the preparation of compound of formula II is selected

from quaternary ammonium salts, crown ethers or any other catalyst used for the same purpose.
9. The process of claim 1 wherein first solvent system for step c for the
purification of compound of formula II comprises solvent and anti
solvent, the said solvent is an ester and said anti-solvent is an aliphatic
alicyclic or cyclic hydrocarbon.
10. The process of claim 9 wherein solvent is ethyl acetate and antisolvent is cyclohexane.
11. The process of claim 1 step d wherein solvent used for the preparation of compound of formula III is selected from group comprising C1-C6 alcoholic solvent, ketonic solvent, ester solvent selected from the group comprising methanol, ethanol, n-propanol, isopropanol, acetone, methyl ethyl ketone, ethyl acetate and mixture thereof.

12. The process of claim 11 wherein solvent is acetone.
13. The process of claim 1 step e wherein second solvent system used for the purification of compound of formula III comprises solvent and anti solvent wherein the said solvent is an alcohol solvent and said anti-solvent is an ethereal solvent.
14. The process of claim 13 wherein solvent is isopropanol and
antisolvent is methyl tert butyl ether.