FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE 2003
(SECTION 10 and rule 13)
PROVISIONAL SPECIFICATION
A PROCESS FOR THE PREPARATION OF STRONTIUM RANELATE

BACKGROUND OF THE INVENTION Technical Field
The present invention relates to an improved process for synthesis of strontium ranelate
or hydrates thereof. More particularly the present invention relates to an effective process
for preparation of intermediate compound of formula III, which is useful in synthesis of
strontium ranelate. •"

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U.S. Patent No. 7,091,364 discloses the process for preparation of intermediate tetraester compounds including the compound of formula II, from reaction of compound of formula III with compound of formula IV (wherein R' is linear or branched alkyl) in an organic solvent in presence of quaternary ammonium compounds at reflux temperature.
In the art, the compound of formula III is prepared by the reaction of 1, 3-acetonedicarboxylic acid diethyl ester, malononitrile and sulfur in ethyl alcohol in the presence of bases like morpholine or diethyl amine. The compound of formula III is reported 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 III obtained may be ascribed to the poor stability of these enolate intermediates formed during the reaction.
Accordingly, the present inventor discovered a novel stable enolate intermediate compound of formula V and its use for preparation of compound of formula III with good yield.
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in an organic solvent in the presence of imidazole to form a compound or formula V-a.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides a process for the preparation of compound of formula III,
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wherein R1 and R2 represents substituted or unsubstituted linear or branched Ci-C6 alkyl
group or C3-C12 cyclic group,
the process comprising the reaction of compound of formula VI,

wherein Rt and R2 represents substituted or unsubstituted linear or branched Ci-C6 alkyl group or C3-C12 cyclic group, with compound of. formula VII, in the presence of imidazole,

via formation of intermediate compound of formula V,

wherein R| and R2 represents substituted or unsubstituted linear or branched Cj-Cs alkyl group or C3-C12 cyclic group.
The C\-C$ alkyl group may be substituted or unsubstituted linear or branched and is, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondry butyl or tertiary butyl, pentyl, hexyl and the like. ■
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The C3-C12 cyclic group may be substituted or unsubstituted and is, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and their halo, nitro, amino derivatives and the like.
In another embodiment the present invention provides a process for the preparation of a compound of formula V ~

Advantageously the organic solvent used is selected from C1-C4 alcohols, for example methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol or mixtures thereof.
In yet another embodiment, the reaction of compound of formula VI and VII can be carried out at room temperature and rection mixture obtained is stirred at 25 - 60 °C for 1 to 4 hours. The amount of imidazole is from 1 to 3 mole equivalent with respect to compound of formula VII. The amount of imidazole is preferably 1 mole per mole compound of formula VII. To this sulfur is added at reflux temperature for about 8-14 hours. The reaction can be worked up conventionally by the concentration of the reaction
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mass and compound of formula V can be isolated by tritutation with a solvent like isopropyl alcohol.
In yet another embodiment, the reaction of compound of formula VI and VII can be carried out at room temperature and rection mixture obtained is stirred at 25 - 60 °C for about 1 to 4 hours. The reaction can be worked up conventionally by the concentration of the reaction mass and compound of formula V-a can be isolated by tritutation with, a solvent like methyl isobutyl ketone.
In yet another embodiment, the present invention relates to a compound of formula V.

OR.

o"

It is believed that as the positive charge of the imidazole moiety is delocalized due to resonance and stability of enolate intermediate compound of formula V-a addition salt is enhanced. This stable enolate intermediate compound of formula V-a can be isolated or used in-situ, which further reacts with sulfur to provide compound of formula III (wherein R] and R2 is methyl),
In yet another embodiment, present invention provides highly pure 5-amino-4-cyano-2-(methoxycarbonyl)-3-thiopheneacetic acid methyl ester, compound of formula III, having a HPLC purity of above 99%.
Compound of formula Il-a can be prepared from compound of formula III by the method known in the art, U.S. Patent No.7,019,364 and related EP Patent No.1403265 Al, incorporated herein by reference.
For example the process for preparation of compound of formula Il-a, comprising reacting compound of formula III,



wherein R represents linear or branched Ci-Ce alkyl group in the presence of catalytic amount of potassium iodide, in the presence of potassium carbonate at 35 - 40 °C in an organic solvent or mixture of organic solvent
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In yet another embodiment, present invention provides a process for the preparation of strontium ranelate or hydrates of compound of formula I, comprising reacting a
compound of formula Il-a,

. R4OOC
11-a wherein R1, R2, R3, and R4 represents substituted or unsubstituted linear or branched Cr C6 alkyl group or C3-C12 cyclic group, in the presence of a-lithium base and in a solvent with an inorganic acid salt of strontium.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
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Comparative Example Preparation of 5-amino-4-cyano-2-(methoxycarbonyl)-3-thiopheneacetic acid methyl
ester
A mixture of malononitrile (15.5 g) and morpholine (20.4 g) was added to a solution of 1,3-acetone dicarboxylic acid dimethyl ester (50 g) in the methanol (86 ml) at room temperature. This reaction mixture was stirred at 40 - 45 0C for 1 to 2 hour. Thereafter, sulfur (7.5 g) was added and the reaction mass was heated to reflux for 10-12 hours. Reaction mass was cooled and filtered and the filtrate was concentrated under reduced pressure. Water was added to the residue and the precipitated solid was isolated by filtration. The solid was further recrystallized from isopropyl alcohol to get 45 g (61%) of 5-amino-4-cyano-2-(methoxycarbonyl)-3-thiopheneacetic acid methyl ester.
Example 1 Preparation of 3-(dicyanomethylene)-5-hydroxy-5-methoxy-4- pentenoic acid methyl ester compound with imidazole (1:1) (Compound V-a)
A mixture of malononitrile (3.6 g) and imidazole (3.7 g).was added to a solution of 1,3-acetone dicarboxylic acid dimethyl ester (10 g) in the methanol (150 ml) at room temperature. This reaction mixture was stirred at 40-45 °C for 1 hour. Thereafter the reaction mass was concentrated under reduced pressure. The residue mass was further triturated with methyl isobutyl ketone to get 6 g of compound V-a, with purity 99% by HPLC.
IR (KBr) cm"': 2166.55 & 2193.89 (2 x CN), 1727.89 (CO), 1157.2 (-O-CH3) and 'H-NMR (proton NMR) having the values as follows: 1H-NMR(DMSO-d6), δ (ppm): 3.41(s, 2H, -CH2-), 3.56 and 3.70(2s, 6H, 2 x -OCH3), 5.04 (s, 1H, =CH-), 7.68 and 9.06(2s, 3H, imidazole hydrogens)
Example 2 Preparation of 5-amino-4-cyano-2-(methoxycarbonyI)-3-thiopheneacetic acid methyl
ester
A mixture of malononitrile (54.1 g) and imidazole (58.48 g) was added to a solution of 1,3-acetone dicarboxylic acid dimethyl ester (150 g) in the methanol (2000 ml) at room
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temperature. This reaction mixture was stirred at 40 - 45 °C for 1 to 2 hour. Thereafter, sulfur (26.25 g) was added and the reaction mass was heated to reflux for 10-12 hours. Reaction mass was cooled and filtered and the filtrate was concentrated under reduced pressure. Water was added to the residue and the precipitated solid was isolated by filtration. The solid was further recrystallized from isopropyl alcohol (750 ml) to get 161 g of 5-amino-4-cyano-2-(methoxycarbonyl)-3-thiopheneacetic acid methyl ester with purity more than 99% by HPLC.

Batch No. Purity Yield
1 99.78 % 73.52%
2- 99.74 % 73.52%
3 99.74 % 73;98%
Example 3 Preparation of 5-[bis (2-ethoxy,-2-oxoethyl) amino]-4-cyano-2-(methoxycarbonyl)-3-thiopheneacetic acid methyl ester
5-amino-4-cyano-2-(methoxycarbonyl)-3-thiopheneacetic acid methyl ester (50 g) was dissolved in a mixture of acetonitrile (200 ml) and dimethylsulfoxide (20 ml) at room temperature. To this solution,.a mixture of potassium iodide (2.5 g) and potassium carbonate (68 g) was added. Thereafter, ethyl bromoacetate (75 g) was added to the reaction mass and reaction mass was stirred at 35 - 40°C for ~7 hours. The reaction mass was then cooled and filtered. The filtrate was concentrated and triturated with isopropyl alcohol. The resulting solid was filtered and dried to get 60 g of 5-[bis (2-ethoxy-2-oxoethyl) amino]-4-cyano-2-(methoxycarbonyl)-3-thiopheneacetic acid methyl ester having purity more than 99 % as determined by HPLC.
Example 4 Preparation of 5-[bis (carboxymethyl) amino]-2-carboxy-4-cyano-3-thiopheneacetic acid distrontium salt
A mixture of 5-[bis (2-ethoxyr2-oxoethyl) amino]-4-cyano-2-(methoxycarbonyl)-3-thiopheneacetic acid methyl ester (50 g) and tetrahydrofuran (250 ml) was cooled to 0-5
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°C. To this mixture, 10% w/v aqueous lithium hydroxide solution (200 ml) was added and the reaction mass was stirred at 0-5°C for ~8 hours. After completion of the reaction, a solution of strontium chloride (71 g) in water (300 ml) was added at 0-5 °C. This reaction mixture was stirred for 15 to 20 hours at room temperature. The precipitated solid, distrontium salt of 5-[bis (2~ethoxy-2-oxoethyl) amino]-4-cyano-2-(methoxycarbonyl)-3-thiopheneacetic acid was filtered off and washed with water. The resulting wet material was dried at 30-35 °C under reduced pressure to yield 55 g of strontium ranelate octahydrate having purity greater than 99.5% as determined by HPLC.
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The present invention particularly provides:
A. A Process for the preparation' of 5-amino-4-cyano-2-(methoxycarbonyl)-3-thiopheneacetic acid methyl ester, a compound formula HI,

V which is further reacted with sulfur to provide a compound of formula III.
B. The process as defined in 'A' wherein organic solvent is selected from C1-C4 alcohol.
C. The process as defined in 'A' wherein the compound of formula V is isolated.
D. A Process for preparation of strontium ranelate or hydrate thereof by using compound
of formula III prepared by process 'A' above.
E. Strontium ranelate or hydrate thereof having purity of more than 99.5% by HPLC,
prepared by process described in 'D' above.
F. The compound of Formula V-a.
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V-a
G. A Process for the preparation of 3-(dicyanomethylene)-5-hydroxy-5-methoxy-4-pentenoic acid methyl ester compound with imidazole (1-:1), a compound formula V-a,
OMe

in an organic solvent in the presence of imidazole to
H. The process as defined in (G' wherein organic solvent is selected from C1-C4 alcohol.

th,
Dated this Eighteenth (18in) day of Aug, 2008

(Signed).
DR. Madhavi Karnik DY General Manager - IPM Glen mark Generics Limited
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