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: A NOVEL PROCESS FOR THE PREPARATION OF STRONTIUM RANELATE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF.
2. APPLICANT:

(a) NAME: ARCH PHARMALABS LIMITED
(b) NATIONALITY: INDIAN
(c) ADDRESS: "H" WING, 4TH FLOOR, TEX CENTRE,
OFF SAKI VIHAR ROAD, CHANDIVALI, ANDHERI (EAST), MUMBAI-400072, INDIA.
PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

TITLE: A novel process for the preparation of strontium ranelate of formula I.
TECHNICAL FIELD OF THE TECHNOLOGY: Disclosed herein is an
improved, commercially viable and industrially advantageous novel
process for the preparation of strontium ranelate of formula I chemically
known as distrontium 5-[bis(2-oxido-2-oxoethyl)amino]-4-cyano-3-(2-
oxido-2-oxoethyl)thiophene-2-carboxylate or 5-

Formula II
wherein Rl and R2 are C1-C8 alkyl group and R' and R" are same or different and is selected from H, C-l to C-6 alky], carbocyclic, heterocyclic groups.

Formula HI X is halogen R',R" are same or different and are selected from H, C-l to C-6 alkyl, carbocyclic, heterocyclic groups.
[bis(carboxymethyl)amino]-2-carboxy-4-cyano-3-thiopheneacetic acid distrontium salt and its intermediates, in high yield and purity comprising using 2-chloro acetamide of formula III as a starting material to prepare a novel compound of formula II as an intermediate and employing the said novel intermediate to prepare strontium ranelate of formula I.

BACKGROUND OF THE INVENTION:
Strontium ranelate, the bis-strontium salt of ranelic acid has proved to have very valuable pharmacological and therapeutic properties, especially pronounced anti-osteoporotic properties. It has dual effects on bone metabolism, by increased bone formation and decreased bone resorption, resulting in rebalance of bone turnover in favor of bone formation. These properties make strontium ranelate very useful in the treatment of bone diseases. Strontium ranelate (Protelos®, Servier Laboratories) is licensed for the treatment of postmenopausal osteoporosis to reduce the risk of vertebral and hip fractures. It has a novel mode of action, both increasing bone formation and reducing bone resorption. One 2.0 g oral sachet should be taken daily in a glass of water, at bedtime, at least 2 hours after eating as its absorption is reduced by food, milk and other calcium-containing products. Patients should also take calcium and vitamin D supplements if their dietary intake is inadequate. It is currently only licensed for use in postmenopausal women; its efficacy and safety have not been demonstrated in other patient groups. No dosage adjustment is required in the elderly. An in depth study found that strontium ranelate is 17 times better at boosting bone formation than the medication usually given to sufferers of the crippling condition. It is also far easier to take than the recommended drug, which requires patients to stand or sit for half an hour after taking it and can cause stomach pains.
EP 0415850 and related U.S. Patent No. 5,128,367 disclose the synthesis of strontium ranelate for the first time. Since then, further processes of the preparation have been described (for example in WO 2004/029036, WO 2007/020527, US 2009/082578).
EP 0415850 discloses three ways for the synthesis of strontium ranelate starting from the ethyl tetraester of ranelic acid of formula IV. Ethyl tetraester of ranelic acid of formula IV is prepared comprising the

reaction of ethyl-2-bromoacetate of formula V as key raw material with ethyl-5-amino-4-cyano-3-(2-ethoxy-2-oxoethyl)thiophene-2-carboxylate of formula VI as shown below:

ethyl 5-amino-4-cyano-3-(2-cthoxy-2-oxocthyl) ethyl 2-bromoacctate
thiophcnc-2-earboxyla tc V
VI

Formula IV

The first process comprises heating the ethyl tetraester of ranelic acid of formula IV with sodium hydroxide at reflux in an aqueous alcoholic medium converted into its sodium salt. The said sodium salt on acidification gave ranelic acid of formula (VII). The acid of formula VII obtained is thereafter converted into strontium ranelate using strontium hydroxide or strontium chloride in water.


Process I of EP0415850:

Another process for preparing strontium ranelate disclosed in EP 0415850 comprises heating the ethyl tetraester of ranelic acid of formula IV at reflux in a 50/50 mixture by volume of a normal sodium hydroxide solution and ethanol, distilling off the solvents to obtain the tetrasodium salt which is thereafter treated with an aqueous solution of strontium dichloride to obtain strontium ranelate.
Process II of EP 0415850:

Yet another process for preparing strontium ranelate disclosed in EP 0415850 comprises heating the ethyl tetraester of ranelic acid at reflux in an aqueous alcoholic medium with strontium hydroxide.
Process III of EP 0415850:


The process disclosed in EP0415850 requires heating at higher temperature which generate impurities and the product obtained doesn't meet today's pharmaceutical requirements. Another industrial problem is that a large amount of solvents is used in reactions and in purification processes and the 4-26 % of the organic solvents may solvate the product. One more industrial problem is the use of ethyl-2-bromoacetate which is not only expensive but also lacrymetric material. The filtration of the intermediates and products by known processes is usually carried out at high temperature because the hydrolyzing agent must remain dissolved to avoid the formation of inorganic salt impurities.
WO2004/029036 discloses a process wherein the ethyl tetraester of ranelic acid of formula IV is reacted with strontium hydroxide at reflux in an aqueous medium. The purity of the strontium ranelate obtained is 98%.

One of the disadvantages of the process is the high temperature of hydrolysis which generates the impurities; therefore, the purity of the product doesn't meet the requirements of today's pharmaceutical industry. Another disadvantage is that strontium hydroxide is poorly soluble in water and therefore the product remains contaminated with inorganic salts. The strontium salts of the intermediates generated in hydrolysis are poorly soluble in aqueous medium as well, and so, they separate out from reaction mixture to provide a poorly miscible suspension, in addition these intermediates gets carried forward and contaminate the product.

WO2007/020527 discloses the synthesis of strontium ranelate of formula I using lithium salt of ranelic acid as an intermediate. The first example describes a process wherein the ethyl tetraester of ranelic acid of formula IV is reacted with 10 % aqueous solution of lithium hydroxide in tetrahydrofuran to obtain lithium salt ranelic acid followed by the addition of strontium chloride to the said lithium salt lithium salt of ranelic acid to yield strontium ranelate of formula I.
According to the process disclosed in the second example, the ethyl tetraester of ranelic acid of formula IV is treated with aqueous lithium hydroxide again, then the reaction mixture is distilled to get oily residue to which toluene is added and further distilled to remove water traces. Then a mixture of methanol and ethyl-acetate (1:1) is added to the oily residue and the mixture is cooled to yield lithium salt. The said lithium salt is treated with strontium chloride in aqueous medium to provide strontium ranelate of formula I.

In both processes described hereinabove, tetrahydrofuran is used as a solvent. Tetrahydrofuran is not safe at large-scale production as it can form unstable and explosive peroxides. In addition, lithium has an effect on the central nervous system, and so, the lithium residue must be examined in the final pharmaceutical product.
US2009/082578 discloses first example as hydrolysis of methyl tetraester of ranelic acid of formula IVA with aqueous solution of sodium hydroxide in tetrahydrofuran then aqueous strontium chloride is added to the reaction mixture to provide strontium ranelate. The same

process is carried out in other solvents (acetone, isopropyl alcohol) and with other hydrolyzing agent (potassium hydroxide) as well.

According to the fifth example, methyl tetraester of ranelic acid of formula IVA is reacted with aqueous solution of sodium hydroxide without using an organic solvent at 70°C. The aqueous solution thus obtained is mixed with ethanol and then, it is reacted with aqueous strontium chloride to get strontium ranelate of formula I.

According to the sixth example, methyl tetraester of ranelic acid is reacted with potassium hydroxide at 55-60 °C. Then the solution is dried at 40°C in vacuum, the residue is mixed with the mixture of methanol and ethyl-acetate then it is stirred to obtain a suspension. The said suspension is filtered to provide the potassium salt of ranelic acid. Then the potassium salt is reacted with strontium chloride in aqueous solution of tetrahydrofuran to obtain strontium ranelate.


As described hereinabove, tetrahydrofuran is unsafe in large-scale production as it can form unstable and explosive peroxides. Yet another disadvantage is that the hydrolysis disclosed therein in US 2009/082578 requires heating at higher temperature, which generate impurities.
US7214805 and (M.Wierzbicki et al, Bull. Soc. Chim. (1975), pages 1786-1792) disclose the synthesis of the compound of formula IV, an intermediate for the preparation of strontium ranelate, comprising alkylation reaction of dialkyl-5-amino-4-cyanothiophene-2-3-dicarboxylate compound of formula VI (wherein R1 and R2 is ethyl) with of alkyl-2-bromoacetate of formula V (wherein R' is ethyl) to give a compound of formula IV.

US7091364 discloses the process for the preparation of tetraester compounds, which are intermediates in the preparation of strontium ranelate, including the compound of formula IV comprising reaction of a compound of formula VI with a compound of formula V (wherein R' is linear or branched alkyl) in an organic solvent in the presence of quaternary ammonium compounds at reflux temperature.


US7105683 and (Dinesh W. Rangnekar et.al, J.Chem.Tech. Biotechnol. (1990) 47, pages 39-46) discloses the synthesis of the compound of formula VI, comprising reaction of 1, 3- acetonedicarboxylic acid diethyl ester of formula VIII, malononitrile of formula IX and sulfur in ethyl alcohol in the presence of base like morpholine or diethyl amine. The compound of formula VI is obtained through the formation of an intermediate, an enolate addition salt with bases such as morpholine, diethylamine. The poor to moderate yield of compound of formula VI obtained may be ascribed to the poor stability of said enolate intermediates formed during the reaction.

WO2010021000 discloses an improved process for the preparation of compound of formula VI comprising preparing a stable enolate of formula X particularly formula XL The said stable enolate yields a compound of formula VI in good yield and high purity, which intern yields final strontium ranelate with high purity for pharmaceutical use.


WO2011124992Aldiscolses impurities those are formed during the preparation of strontium ranelate by the processes available in the prior art. It also discloses the methods to eliminate the said impurities.
Strontium ranelate and its intermediates obtained by the processes described therein above in the prior art do not have desired purity. Unacceptable amounts of impurities are generally formed during the synthesis of strontium ranelate. There are evolving and more rigorous requirements demanded by drug manufacturers and with the prevailing disadvantages present with the processes disclosed therein in 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 ensuring a target strontium ranelate product with optimum yield and purity. One of the notable drawback for the preparation of compound of formula IV is the use of alkyl-2-bromoacetate of formula VI which is not only expensive (five times costlier than the raw material used in the subject invention) but also lacrymatric.

The objective of the present invention is to avoid using alkyl-2-bromoacetate of formula VI as a starting material and also to provide a industrially safe, economical process for the preparation of substantially pure pharmaceutical grade strontium ranelate minimizing or eliminating the formation of impurities. While working on theme; two routes were considered:
One route comprises using compound of Formula C as a raw material:

Formula C
The ROS in accordance with using compound of Formula C as a raw material is given below:

The other route comprises using compound of Formula III as a raw material:

Formula III X is halogen R\R" are same or different and are selected from H, C-l to C-6 alkyl, carbocyclic, heterocyclic groups.
The ROS in accordance with using compound of Formula III as a raw material is given below:


*The said reaction also proceeds well resulting into the desired compound of formula I using strontium chloride in place of strontium hydroxide.
However, it has been observed by the inventors of the instant subject invention that in case of first route wherein compound of Formula C is used as a raw material it results into the formation of an impurity resulting from the hydrolysis of the cyanide group at the position 4 forming penta carboxylic compound as a major impurity as shown herein below:

In view of above the novel process proposed herein above comprises using compound of Formula C as a raw material does not provide solution to the problems associated with the processes disclosed therein in the prior art.

The inventors of the present invention therefore, provide herein a novel process for the preparation of substantially pure strontium ranelate of formula I or hydrate thereof comprising using compound of Formula III as a key raw material to obtain a novel compound of Formula II and the said novel compound of Formula II is employed to prepare strontium ranelate of formula I or hydrate thereof.

The process under the invention comprises use of easily available, cost effective, industrially feasible, non-lacrymatric raw material.
OBJECT OF THE INVENTION:
In one aspect, provided herein is a novel, efficient, commercially viable
and environment friendly process for the preparation of pure strontium
ranelate, distrontium salt of 5-[bis(carboxymethyl)amino]-3-
carboxymethyl-4-cyano-2- thiophenecarboxylic acid, OR 5-
[bis(carboxymethyl)amino]-2-carboxy-4-cyano-3- thiopheneacetic acid distrontium salt of formula I substantially free of impurities

In second aspect, provided herein is a process for the preparation of a novel compound of formula II using raw material of formula III.
In third aspect, provided herein is a process for the preparation of a novel compound of formula II with its characterization and structure elucidation.
In forth aspect, provided herein is a process for the preparation of strontium ranelate comprising use of novel intermediate of the formula III.
In fifth aspect, provided herein is a process for purification of intermediates and its use to make strontium ranelate to reduce or completely eliminate the potential impurities, which are formed during the synthesis of strontium ranelate and its intermediates.
In sixth aspect, provided herein is a substantially pure strontium ranelate substantially free from impurity A.
In seventh aspect, provided herein is a novel process for the preparation of ranelic acid of formula VII and its salts, an intermediate for the preparation of strontium ranelate.
In eighth aspect, disclosed herein are novel impurities, and a novel intermediate of formula II.
SUMMARY OF THE INVENTION:
The subject invention provides a novel process for the preparation of strontium ranelate of the formula I comprising the use of key raw material of formula III yielding novel intermediate of formula II. The entire process is depicted hereinbelow in the following scheme:


Details of the novel process for the preparation of substantially pure strontium ranelate of the formula I are given in detailed description.
DETAILED DESCREPTION OF THE INVENTION:
Disclosed herein is a novel process for the preparation of Strontium ranelate of the formula I comprising the use of a novel raw material of formula III. It further provides a novel intermediate of Formula II and a process for the preparation of novel intermediate of formula II.
A general embodiment the subject invention discloses a process for the preparation of strontium ranelate of formula I comprising:
a) contacting malononitrile of formula IX with 1, 3- acetonedicarboxylic acid dialkyl ester of formula VIII and sulphur in presence of a base and a solvent to obtain compound of formula VI;


b) contacting dialkyl-5-amino-4-cyanothiophene-2-3-dicarboxylate compound of formula VI obtained in step a with substituted haloacetamide of formula III in a solvent and in the presence of a base, a phase transfer catalyst in combination with alkali metal halides to obtain novel intermediate of formula II;

c) hydrolysing optionally purified diamide diester of formula II with a alkali metal base to obtain alkali metal salt of ranelic acid of formula VIIA;

d) contacting optionally isolated alkali metal salts of formula VII A from step d with strontium source to obtain strontium ranelate of formula I.

In another general embodiment the subject invention discloses a process for the preparation of strontium ranelate of formula I comprising:
a) contacting malononitrile of formula IX with 1, 3- acetonedicarboxylic acid dialyl ester of formula VIII and sulphur in presence of a base and a solvent resulting into the formation of compound of formula VI;

b)contacting dialkyl-5-amino-4-cyanothiophene-2-3-dicarboxylate
compound of formula VI obtained in step a with substituted haloacetamide of formula III in a solvent and in the presence of a base, a phase transfer catalyst in combination with alkali metal halides to obtain novel intermediate of formula II;

c) hydrolysing optionally purified diamide diester of formula II with a base to obtain ranelic acid of formula VII;


d) optionally isolating and contacting the compound of Formula VII obtained in step c with alkali metal base to obtain the corresponding alkali metal salt of compound of Formula VIIA;

e) contacting alkali metal salts of formula VII A from step d with strontium source to obtain strontium ranelate of formula I.
In one more general embodiment of the subject invention disclosed
herein is a process for the preparation of strontium ranelate of formula I
comprising:
c) contacting optionally purified diamide diester of formula II directly
with strontium source resulting into formation of strontium ranelate of
formula I;


Base used for the reaction of compounds of formulae VIII and IX used in all the general embodiments described herein above is selected from the group comprising morpholine, diethylamine, imidazole and the like.
The solvent used for the reaction of compounds of formulae VIII and IX used in all the general embodiments described herein above is selected from the group of C1-C4 alcohol preferably methanol.
Dialkyl-5-amino cyanotetrahydrothiophene-2-3-dicarboxylate compound of formula VI used in both the general embodiments described herein above is selected from C1-C8 linear or branched alky group, cyclic alkyl, aryl, substituted aryl groups.
Substituted haloacetamide of formula III used in all the general embodiments described herein above is selected from group comprising 2-chloroacetamide, 2-bromoacetamide, 2-iodoacetamide and the like. R' is selected from H, C-l to C-6 alkyl, carbocyclic, heterocyclic groups.
Solvent used in all the general embodiments described herein above comprising the reactions of compounds of formulae VI and III to prepare the compound of formula II could be one that will not react with any of the reactant used in the whole process selected from group comprising dimethyl formamide, dimethyl acetamide, , N-methyl pyrolidinone, acetone, acetonitrile, dioxane, tetrahydrofuran alkylesters and mixture thereof preferably dimethyl formamide.

Alkali metal halide used in the general embodiments is selected from the group comprising alkali metal halides like bromides, iodides etc. Alkali metal halide preferably iodide used as Iodine source used in all the general embodiments described herein above is one that will undergo the trans-halogenation with 2-halosubstituted acetamide generating 2-iodoacetamide that accelerates the rate of said reaction as per the scheme depicted herein below. Iodine source is preferably selected from group comprising lithium iodide, potassium iodide, sodium iodide and the like.

A phase transfer catalyst used in all the general embodiments described herein above is selected from group comprising quarternary ammonium salts, Crownethers preferably tri methyl butyl ammonium chloride.
It has been observed by the inventors of the subject invention that for the preparation of compound of Formula II only presence of quaternary ammonium alone does not take the said reaction ahead but the presence of iodide source plays a vital role. The probable reason for the said observation may be transhalogenation (discussed above) that results into iodine compound of formula III. Iodine being a better leaving group accelerates the rate of reaction.
The base used in all the general embodiments described herein above comprising the reaction of compounds of formulae VI and III for the preparation of compound of formula II is selected from group comprising alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, alkalimetalphosphates alkaline earth metal

hydroxides, alkaline earth metal carbonates, alkaline earth metal bicarbonates preferably alkali metal hydroxides.
It has been observed by the inventors of the subject invention that use of alkali metal carbonates results into the best of the results in terms of yield and purity. Use of alkali metal hydroxide at the temperature above 70-80°C results into formation of probable Michael adducts as impurity I or impurity II as depicted herein below.

The base used for the hydrolysis of diamide diester of the formula II to prepare ranelic acid of formula VII as described in general embodiments herein above is selected from group comprising alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides
It has been observed by the inventors of the subject invention that use of alkali metal carbonates like potassium carbonate requires external heating at about 70-80°C and also long duration. On the other hand in case of alkali metal hydroxides such as sodium hydroxide the hydrolysis proceeds well without any external heating in a shorter duration. However it is important to note that excessive heating or high temperature results into the formation of a probable impurity (Impurity II). The probable mechanism for its formation is depicted herein


below.
Strontium source used in all the general embodiments described herein above is selected from strontium salts comprising strontium halides, carbonates, bicarbonates, hydroxides and the like.
However it is important to note that diamide diester of formula II when insitu treated with strontium hydroxide it produces impure strontium ranelate, this may be because of trapped strontium carbonate generated by reaction of unreacted potassium carbonate from the step b and strontium hydroxide.

Secondly when diamide diester of formula II when directly treated with strontium hydroxide without isolating ranelic acid it also produces impure strontium ranelate, this may be due to insufficient/ partial hydrolysis of diester diamide of formula II.


Temperature of the reaction is to be such that it should not destroy the reaction. But it is to be optimum temperature that will result into the maximum conversion of reactants without formation of multiple numbers of side products.
The process disclosed herein eliminates the formation of the impurity -I or II. It has been observed by the inventors of the subject invention that all the impurities as disclosed by WO2011124992A1 are not formed as '992 follows the prior art synthesis comprising the use of tetra ester of formula IV as key intermediate.
In the subject invention; inventors have found that the most prominent impurity that is possible to get formed by novel process disclosed herein is II. The said impurity II emerges as depicted in the scheme given below:

In an embodiment of the subject invention; inventors have proposed a process for the purification of diester diamide intermediate of formula II by using one or more solvents. The solvent used for the purification of

the novel intermediate of formula II is selected from group comprising polar solvents like water, alcohol, ester, ketones, amides, ethers and non polar solvents like aromatic solvents like toluene etc.
In an embodiment of the subject invention; inventors have proposed a process for the purification of ranelic acid, an intermediate of formula VII for the preparation of strontium ranelate. Owing to high solubility of ranelic acid in water, selected mode of purification of ranelic acid is either through the single solvent or by concept of solvent and antisolvent.
Solvent used for the purification of ranelic acid of formula VII is any solvent in which ranelic acid is appreciably soluble and anti solvent is any solvent that can precipitate ranelic acid from the dissolved solution.
The invention is best understood by the following example:
Dimethyl-5-amino cyanotetrahydrothiophene-2-3-dicarboxylate used in the process can be prepared by any method available in literature (M.Wierzbicki et al, Bull. Soc. Chim. (1975), 1786-1792).
1. Preparation of intermediate of formula II: (5-[bis(2-amino-2-oxoethyl)amino]-4-cyano-2-(methoxycarbonyl)-3-thiopheneacetic acid methyl ester) OR [Methyl 5-(bis(2-amino-2-oxoethyl)amino)-4-cyano-3-(2-methoxy-2-oxoethyl)thiophene-2-carboxylate.]


To a well stirred suspension of dimethyl-5-amino -4-cyanothiophene-2-3-dicarboxylate (30g, 0.118 mol) and K2C03 (40.7g, 0.295 mol) in DMF (300 mL) was added KI (1.0 g) and Tri methyl butyl ammonium chloride (250 mg) and stirred at room temperature for 10 min. 2-Chloroacetamide (44.1 g, 0.47 mol) was added to above reaction mass in one lot and stirred at 60 °C for 24 h. The reaction mixture was filtered and solid cake was washed with DMF (15 mL). DMF was removed under reduced pressure to yield dark brown solid which was crystallized from IPA to yield pale yellow compound (36.4g, 82 % with 99.5% HPLC purity).
1H NMR(Varian, 400 MHz, DMSO) 5 3.639(s, 3H, -OCH3), 3.733 (s,
3H, -OCH3), 3.974(s, 2H, CH2), 4.270(s, 4H, 2x NCH2), 7.361 and
7.963 2 x (s,2H,NH2)ppm.
13C NMR(Varian, 400 MHz, DMSO) 33.937, 52.522, 58.399, 88.546,
110.600, 115.463, 144.130, 161.430,166.347,169.530 and 169.684
ppm.
IR spectrum (Shimadzu 8400s, KBr) 1251, 1271, 1317, 1514, 1556,
1624, 1675, 1712, 1734, 2202, 2958, 3221and 3317 cm-1.
Mass Spectral Data (LCMS Thermofinnigan, LCQ advantage Max,
APCI probe, +ve mode) Observed molecular ion peak at m/z = 368.8
(M+H).
2. Preparation of Strontium Ranelate (Direct method).


To an aq. solution of strontium hydroxide (prepared by dissolving Sr(OH)2.8H20, 10.8 g, 0.04 mol in 275 mL of water) was added (5-[bis(2-amino-2-oxoethyl)amino]-4-cyano-2-(methoxycarbonyl)-3-thiopheneacetic acid methyl ester (II) (5 g, 0.013 mol) at room temperature. The suspension was stirred for 30 h at 80-85 °C and then filtered at 45 °C to obtained white strontium ranelate (80% yield with purity 96%)
3. Preparation of Ranelic acid of formula VII:

To a well stirred suspension of (5-[bis(2-amino-2-oxoethyl)amino]-4-cyano-2-(methoxycarbonyl)-3-thiopheneacetic acid methyl ester (II) (5.0 g, 0.013 mol suspension in 25 mL water ) was added aq. NaOH (3.26 g dissolved in 25 mL water) dropwise at 5-10 °C during 1 h. The reaction mixture was allowed to warm at room temperature and stir for 48 h. The aq. layer was further acidified and extracted with ethyl acetate twice and combined ethyl acetate layer was concentrated under reduced pressure to yield beige color compound (4.4 g, 95% yield, purity 98.5 %).
4. From Ranelic acid to Strontium Ranelate:


To a solution of strontium hydroxide (prepared by dissolving Sr(OH)2.8H20, 8.54 g, 0.032 mol in 272 mL of water) was added Ranelic acid (VII) (4.4 g, 0.013 mol) at room temperature. The suspension was stirred for 6 h at 80-85 °C and then filtered at 45 °C to obtained white strontium ranelate (85% yield with purity 99.5%)
5. Preparation of Strontium Ranelate using strontium chloride:

To a well stirred suspension of (5-[bis(2-amino-2-oxoethyl)amino]-4-cyano-2-(methoxycarbonyl)-3-thiopheneacetic acid methyl ester (II) (10 g, 0.027 mol) in 50 mL water was added aq. NaOH (6.51 g, 0.162 mol dissolved in 50 mL water) dropwise at 5-10 °C during 1 h. The reaction mixture was allowed to warm at room temperature and stir for 48 h. Reaction mass was filtered off and aq. layer was treated with aq. strontium chloride solution (22.66 g, 0.085 mol in 100 mL water) at room temperature for 24 h. and then filtered to obtain strontium ranelate (84% yield with purity 99.5 %).
Confirmation of the formation of strontium ranelate prepared by following the novel process described therein the specification is given on the basis of its chromatograph with reference standard in spite of giving the NMR as it does not have the proper solubility and hence does not give proper NMR.

Figure I represent 1H NMR of diester diamide of formula II.
Figure II represent 13C NMR of diester diamide of formula II.
Figure III: represent IR of diester diamide of formula II.
Figure IV: represent LCMS of diester diamide of formula II.
Figure V: represent 1H NMR of Ranelic acid prepared from diamide diester.
Figure VI: represent 1H NMR of Ranelic acid prepared from tetraester.
Figure VII: represents HPLC chromatograph showing the same retention time for the standard reference of strontium ranelate and strontium ranelate prepared by the novel route under the instant subject invention thereby confirming the molecule strontium ranelate.

Spectral data:
Figure I: 1H NMR of Diester diamide of formula II

Figure II: 13C NMR of Diester diamide of formula II


Figure III: IR of diester diamide of formula II

Figure IV: LCMS of diester diamide of formula II


Figure V: 1H NMR of Ranelic acid prepared from diamide diester

Figure VI: 1H NMR of Ranelic acid prepared from tetraester


Figure VII: HPLC of strontium ranelate


CLAIMS:
1. A process for the preparation of substantially pure compound of
Formula I

comprising:
a) contacting malononitrile of formula IX with 1, 3- acetonedicarboxylic acid dialkyl ester of formula VIII and sulphur in presence of a base and a solvent to obtain compound of formula VI;

Rl and R2 are C1-C8 alkyl group
b) contacting dialkyl-5-amino-4-cyanothiophene-2-3-dicarboxylate compound of formula VI obtained in step a with substituted haloacetamide of formula III in a solvent and in the presence of a base, a phase transfer catalyst in combination with alkali metal halides to obtain novel intermediate of formula II;



c) hydrolysing optionally purified diamide diester of formula II with a base to obtain ranelic acid of formula VII;

d) optionally isolating and contacting the compound of Formula VII obtained in step c with alkali metal base to obtain the corresponding alkali metal salt of compound of Formula VIIA;

e) contacting alkali metal salts of formula VII A from step d with strontium source to obtain strontium ranelate of formula I.
2. A process for the preparation of substantially pure compound of Formula I


comprising:
a) contacting malononitrile of formula IX with 1, 3- acetonedicarboxylic acid dialkyl ester of formula VIII and sulphur in presence of a base and a solvent to obtain compound of formula VI;

Rl and R2 are C1-C8 alkyl group
b) contacting dialkyl-5-amino-4-cyanothiophene-2-3-dicarboxylate compound of formula VI obtained in step a with substituted haloacetamide of formula III in a solvent and in the presence of a base, a phase transfer catalyst in combination with alkali metal halides to obtain novel intermediate of formula II;



c) hydrolysing optionally purified diamide diester of formula II with a alkali metal base to obtain alkali metal salt of ranelic acid of formula VIIA;

d) optionally isolating and then contacting the compound of Formula VIIA with strontium source to obtain strontium ranelate of formula I.
3. The process of claim la and 2a wherein base is selected from the group comprising morpholine, diethylamine, imidazole and the like preferably morpholine.
4. The solvent of the claim la and 2a, wherein solvent is selected from C1-C4 alcohol preferably methanol.
5. The process of claim lb and 2b wherein base is selected from the group comprising alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, alkali metal phosphates alkaline earth metal hydroxides, alkaline earth metal carbonates, alkaline earth metal bicarbonates preferably alkali metal carbonates.

6. The process of claim lb and 2b wherein solvent is selected from group comprising dimethyl formamide, dimethyl acetamide, , N-methyl pyrolidinone, acetone, acetonitrile, dioxane, tetrahydrofuran alkyl acetates and mixture thereof preferably dimethyl formamide.
7.The process of claim lb and 2b wherein phase transfer catalyst is selected from group comprising quarternary ammonium salts, Crownethers preferably Tri methyl butyl ammonium chloride.
8. The process of claim lb and 2b wherein alkali metal halide is selected from the group comprising alkali metal bromides, iodides preferably potassium iodide.
9. The process of claim lc and 2c wherein base used for the hydrolysis is selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, alkaline earth metal hydroxides, alkaline earth metal carbonates, alkaline earth metal bicarbonates, alkali metal phosphates preferably alkali metal hydroxides.
10. A process for the preparation of substantially pure compound of
formula I

comprising:

contacting compound of Formula II with stronsium source to obtain stronsium ranealate of formula I.

11. Strontium source claimed in le, 2d and 9 is selected from the group comprising strontium hydroxide, strontium chloride, strontium acetate preferably strontium hydroxide.
12. A compound of Formula II.