FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
PROVISIONAL SPECIFICATION
(SECTION 10)

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PROCESS FOR INDUSTRIAL SYNTHESIS OF STRONTIUM RANELATE AND ITS HYDRATES THEREOF

Glenmark Pharmaceuticals Limited, an Indian Company,
registered under the Indian company's Act 1957 and
having its registered office at
B/2, Mahalaxmi Chambers, 22, Bhulabhai Desai Road
Post Box No. 26511
Mumbai - 400 026, India
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION

T

FIELD OF THE INVENTION
This invention relates to an improved process for industrial synthesis of pure
Strontium Ranelate and its hydrates of formula-I

0,
o"
NC.

,0
2+
o"
0" Sr"

o
formula-I
(0003] More specifically this invention relates to synthesis of compound of formula-I from a compound of formula-II through formation of compound of formula-Ill


0.
R30 R20

0

NC.
N'

formula-11

O

COOR OR,

Wherein R, R], R2, R3 may be same or different each represents linear, cyclic or branched (d-C6) alkyl.
.0
NC,

0

O

°2Li*

2Li4

0~ O

0

0

formula III

2

BACKGROUND OF THE INVENTION
[0004] The bivalent salts of ranelic acid have very valuable pharmacological and therapeutic properties, especially pronounced anti -osteoporotic properties, making these compounds more useful in the treatment of bone diseases.
[0005] Strontium raneiate, its preparation and its therapeutic use have been described in European patent Specification EP 0415850
[0006] However, industrial production of strontium Raneiate requires detail study of all the reaction steps and of the selection of starting material reagents and solvents in order to obtain optimum yield and good purity of the final product strontium raneiate.
[0007] The patent description describes the synthesis of strontium raneiate from compound of formula-II.
[0008] The starting material of the formula-II is described in the literature (cf.M.Wierzbicki et al. Bull. Soc. Chim. (1975) pages 1786-92)
[00009] The present invention discloses a synthetic process for strontium raneiate by direct conversion of tetra ester compound of formula-II into strontium raneiate under mild conditions optionally isolating the intermediate formula-Ill in good yields and purity of the final compound.
DESCRIPTION OF ART
[0011] The US 5,128,367 patent describes the synthesis of strontium raneiate of formula-I from
tetra ester compound of formula-II by heating at reflux in alcoholic or aq. alcoholic medium in
presence of sodium hydroxide solution then hydrolyzed in an acidic medium to give an acid of
formula-IV.
NC^^y-COOH
HOOC^NAXCOOH
HOOC^
formula-IV
Which is further converted into its sodium salt and finally converted in strontium raneiate using strontium hydroxide or strontium chloride in water
[0012] The patent specification EP0 415 850 describes three methods for this conversion ,which comprising heating the compound of formula-II, in an aqueous alcoholic medium with a base
3

such as sodium hydroxide or strontium hydroxide , and then distilling of the ethanol and isolating the sodium salt of the compound of formula-IV.
[0013] In order to synthesize the strontium ranelate of formula-I on industrial scale , the present invention discloses a simple industrial synthesis process, which allows the compound of formula-I to be obtained in good yield with a shorter reaction time and mild reaction conditions favoring excellent purity in which the isolation of free acid and sodium salt intermediates are completely avoided.
DETAILED DESCRIPTION OF THE INVENTION
[0015] The present invention discloses an effective industrial synthesis process for preparation of strontium ranelate of formula-I from tetra ester compound of formula-II via formation of compound of formula III as in situ .
[0016] The final product strontium ranelate is obtained with a purity greater than 99%, more preferably great than 99.5% and in a yield of more than 85%, which is reproducible on an industrial scale.
|0017] More specifically the tetra ester compound of formula-II is hydrolyzed at room temperature using lithium hydroxide or lithium carbonate more preferably the base used is lithium hydroxide monohydrate
[0020) Solvent used is selected solvents but not limited to tetahydrofuran, 1,3 dioxane, methanol, ethanol, water and mixtures there of , more preferably tetrahydrofuran and water mixture
[0023] The amount of strontium chloride used is preferably from 1 mole to 2.5 moles per one mole of compound of formula-II
|0024] The obtained precipitate is filtered off and washed with water. [0025] The resulted solid is dried to yield the compound of formula-1 and its hydrates. [00XX] In further aspect of the present invention, when a pharmaceutical composition comprising Strontium Ranelate prepared according to the present invention is formulated for oral administration. Accordingly, D50 and D90 particle size of the unformulated Strontium Ranelate or of Strontium Ranelate used as starting material in preparing a pharmaceutical composition generally is less than 400 microns preferably less than about 200 microns, more preferably less
4

than 150 microns, still more preferably less than about 50 microns and still more preferably less
than about 15 microns.
Any milling, grinding micronizing or other particle size reduction method known in the art can
be used to bring the solid state Strontium Ranelate into any desired particle size range as set forth
above.
[0026) The following example contains detailed descriptions of method of preparation of
Strontium Ranelate described herein. These detailed descriptions fall within the scope of the
invention and illustrate the invention without in any way restricting the scope of the invention.
Example 1
[0027| A mixture of tetrahydrofuran (375 ml), 5-(Bis-ethoxycarbonylmethyl-amino)-4-cyano-3-methoxycarbonylmethyl-thiophene-2-carboxylic acid ethyl ester (250 gm) and 1200 ml 10 % aq. solution of lithium hydroxide was stirred at room temperature for about 4-6 hrs in round bottom flask. The reaction mass was filtered off to remove any insoluble material. The clear filtrate further stirred with 2.2 moles of strontium chloride in 1.7 lit of water for 15-20 hrs at room temperature. The precipitated solid, distrontium salt in the form of octahydrate of 2-[N-N-di(carboxymethyl-)amino]-3-cyano-4-carboxymethylthiophene-5-carboxylic acid, is filtered off and followed by washing with water. The resulted wet cake was dried to yield 333 gm of strontium Ranelate octahydrate with purity greater than 99.5% by HPLC.
Dated this Eighteenth (18TH)) day of August, 2005
(Signed) VV^4-
Dr. Swaroop Kumar V. V. S. Head - Drug Discovery & Clinical Development GLENMARK PHARMACEUTICALS LIMITED
5

ABSTRACT
[0053] A process for the preparation of strontium ranelate or a hydrate thereof is
provided comprising (a) reacting a tetraester compound of Formula II
NC ^-COOR
,OR,
(II)
wherein R, R], R2, and Rj are independently a linear or branched C|-Cg alkyl group or a substituted or unsubstituted C3-C12 cyclic group, in the presence of a lithium base and in a solvent with an inorganic acid salt of strontium.
2^2806