The present invention provides an improved process for the preparation of 5-[4-[2-(N'-meth\i-N-(2- pyridyl)amino)ethoxy]-benzyl] -2,4 -thiazolidinedione (Rosiglitazone), and its phamiaceutically acceptable salts.
The present invention, more particularly, provides an improved reduction method for the preparation of Rosiglitazone maleate. The drug may be represented by the fomnila (1):

Formula (1)
Rosiglitazone and its pharmaceutically acceptable salts are useful as pharmaceuticals, in particular, as an insulin-sensitizing agent, for the treatment of diabetes.
Background of Invention
W accordance with the prior art as reported in US 5.002.953 and US Pat. No5, 646.169 method of
•I*,,.,.
preparation of 5-[4-[2-{N-methyl-N-(2-PyridyI)amino)ethoxy]-benzyl] -2,4 -thiazolidinedione maleate of formula (1) is disclosed, which comprises:
1. reduction of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]-benzylidenej-2.4- thiazolidinedione under hydrogen gas in presence of 10% palladium on charcoal.
2. subsequent conversion of the 5[4-[2-(N-methyl-N-(p-pyridyl)amino)ethox>']-benzyl] - 2,4 - thiazolidinedione thus obtained to its pharmaceutically acceptable salts.
It is noteworthy to mention that the procedure disclosed in US 5,002,953 and US Pat. No. 5,646,169 involves, in the first step, high-pressure hydrogenation using a relatively expensive palladium on carbon as catalyst. The present invention provides an improved and more efficient method for performing this reduction, which uses a cobaltous chloride/bidentate Hgand/sodium borohydride catalyst system. This reduction method is convenient for commercial production since no high , pressure apparatus is required.
As Rosiglitazone and its pharmaceutically acceptable salts are useful as pharmaceuticals, in particular, as an insulin-sensitizing agent, for the treatment of diabetes, it is important to have a cost effective, commercially viable and industrially scaleable process for preparing the compound of formula 1.
Therefore, the main objecti\ e of the present invention is to develop a process for preparing the compound of formula 1, which is cost effective, commercially viable and easily scaleable.
Summary of the Invention
Accordingly, the present invention provides an improved process for the preparation of compound of formula (I), which comprises: -
1. reduction of 5-[4-[2-(N-mahyl-N-(2-pyridyl)amino)ethoxy]-benzylidene]-2,4- thiazolidinedione in preseiKe of cobalt ion /bidentate ligand' sodium borohydride/potassium borohydride catalyst system;
2. subsequent conversion of fte5-[4-[2-(N-methyl-N-{2-pyridyl)amino)ethoxy]- benzyl]thiazolidine-2.4 -dione thus obtained to its pharmaceutically acceptable salts in solvents selected fi-om ketOK solvents as acetone or halogenated solvents as chloroform or methylene chloride. The cwiversion may schematically be depicted as follows:
I
i
It is noteworthy to mention that 5-[4-[2-(N-methyl-N-(2-pyridyl)aniino)ethoxy]-benzylidene]-2.4- thiazohdinedione has been prepared by method disclosed in prior art.
The present invention is, hence, directed to an industrially suited, commercially viable and cheaper process.
It is important to mention that the present invention provides Rosigiiiazone of high punty.
"" I
Detailed Description of the Invention
The present invention provides an improved process for the preparation of Rosightazone
maleate, which incorporates steps 1 and 2.
1. "Reduction of 5-[4-[2-(N-methyI-N-(2-pyridyl)amino)ethoxy]-benzylidene]-2,4- thiazolidinedione by a process which comprises:
a. reaction of compound of the formula 2, in presence of aqueous alkali hydroxide selected from sodium hydroxide or potassium hydroxide preferably sodium hydroxide and in presence of a suitable solvent selected from C1-C4 alcohols preferably methanol, with a solution of cobalt ion selected from cobalt chloride hexah\ drate and a ligand selected from dimethyl glyoxime, in dimethyl formamide and a solution of reducing agent selected from sodium borohydride or potassium borohydride preferably sodium borohydride in sodium hydroxide , at a temperature in the range of 0-40'^C preferably 5-20°C for a period of 3-24 hours preferably 4 -6 hours;
b. subsequent addition of water and halogenated solvents selected from methylene chloride or | ethylene chloride preferably methylene chloride, to the reaction mixture obtained in step
a) followed by dropwise addition of acetic acid at 0-40"C preferably 20-25°C, till the pH i
is 4-7 preferably 6-7.
' c. extraction of the aqueous layer of the resultant biphasic system with halogenated solvents
selected from methylene chloride or ethylene chloride preferably methylene chloride:
d. combining the organic layers and subjecting to carbon treatment accompanied by distillation;
e. addition ofketone solvent selected from acetone or C1-C4 alcohols preferably isopropyl alcohol and isolation of Rosiglitazone of formula 3, by filtration.
2. Preparation of Rosiglitazone maleate of formula 1 by a process which comprises:
a. reacting Rosiglitazone of fonnula 3 with maleic acid in ketone solvent selected from acetone or halogenated solvents selected from chloroform or methylene chloride preferably acetone, at their respective reflux temperatures for a period of 15 minutes to 2 hours preferably 20 - 30 minutes;
b. subjecting the clear solution obtained in step a) to carbon treatment;
c. filtering and optionally distilling the solvent to dryness;
d. in case of optional distillation, adding ketone solvent selected from acetone or halogenated soh ents selected from chloroform or methylene chloride preferably acetone and stirring the reaction mixture at a temperature in the range of 0-40^^0 preferably 0-20°C for a penod of 15 minutes to 2 hours preferably 20 - 30 minutes ;
e. isolating the maleate salt by conventional methods.
The present invention is hence directed to an improved process for the preparation of Rosiglitazone Maleate which is high yielding, industrially suited, commercially viable and cost friendly process as:
1. The prior art processes describe in the first step a high-pressure hydrogenation using a relatively expensive palladium on carbon catalyst. The present invention comparatively provides an improved and more efficient method for performing this reduction, which uses a cobalt ionbidentate ligand/sodium borohydride catalyst system. This reduction method is convenient for commercial scale up since no high-pressure apparatus is required.
,2. The present invention also aims at providing a more industrially suited solvcni for
preparation of the maleate salt, rendering the process economical and commercially |
viable.
3. It is also imponant to mention that the present invention provides Rosiglitazone of ;
formula 3 in high purity.
The present invention is described in detail with examples given below which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention. Example:
Step-1: j
Reduction of 5-(4-[2-(N-methyl-N-(2-pyridyI)amino)ethoxy]-benzylidenel-2,4-
thiazoUdinedione:
A mixture 5-[4-[2-(N-methyl-N-{2-pyridyl)amino)ethoxy]-benzylidene]-2,4-thiazolidinedione (20 gm), water (140 ml), methanol (40 ml) and 1.0 N sodium hydroxide (24 ml) is stirred ai 25°C for 15 minutes and then cooled to 10- 15°C. To the reaction mixture is then added, the catai\iic mixture of dimethyl glyoxime (2.6 gm) and cobalt chloride hexahydrate (0.14 gm) in dimethyl formamide (28 ml). Furthermore, a solution of sodium borohydride (4.8 gm) dissolved in 1.0 \ sodium hydroxide (8 ml) and diluted with 40 ml of water, is added. The reaction mixture is then stirred at 10- 15°C for about 4 hours till the conversion is substantially complete. The reaction mixture is then diluted with water (200 ml) and methylene chloride (200 ml) and subjected to dropwise addition of acetic acid (10 ml) to pH 6. Of the resultant biphasic system the aqueous layer is extracted with methylene chloride, the organic layers combined and subjected to carbon treatment accompanied by distillation. To the residue is added isopropyl alcohol (SO ml) and stirred at 0-8° C follow ed by filtration to afford the desired compound. (Yield: 16 gm).
Slep-2:
Preparation of Rosiglitazone maleate
A solution of 5-[4-[2-(N-methyl-N-(2-Pyridyl)amino)ethoxy]-benzyl] -2.- -thiazolidinedione (10 gm) in of acetone (100 ml) is heated to 50 - 55°C accompanied by addition of a solution of maleic acid, prepared by dissolving maleic (3.3 gm) acid in acetone (20 ml). The reaction mixture is stirred at the same temperature for 15 minutes and then subjected to carbon treatment accompanied by filtration. The filtrate is distilled and to the residue obtained is added acetone (20 ml). The reaction mixture is then cooled to 0 °C, stiiTed for 30 minutes and the resultant suspension filtered to afford title compound of formula 1 (Yield: 11 g).

\ye claim:
1. An improved process for the preparation of 5-[4-[2-(N-methy!-N-(2-pyridyl)amino)etho.\y]- benzyI]-2,4-thiazolidinedione maleate (Rosiglitazone maleate (Formula-I)) by a process which comprises :
a) reaction of compound of the foitnula 2, in presence of aqueous alkali hydroxide selected from sodium hydroxide or potassium hydroxide preferably sodium hydroxide and in presence of a suitable solvent selected from C1-C4 alcohols preferably methanol, with a solution of cobalt ion selected from cobalt chloride hexahydrate and a ligand selected from dimethyl glyoxime. in dimethyl formamide and a solution of reducing agent selected from sodium borohydride or potassium borohydride preferably sodium borohydride in sodium hydroxide , at a temperature in the range of 0-40°C preferably 5- 20°C for a period of 3-24 hours preferably 4 -6 hours;
b) subsequent addition of water and halogenated solvent selected from methylene chloride or
ethylene chloride preferably methylene chloride, to the reaction mixture obtained in step a) follow ed by dropwise addition of acetic acid at 0-40°C preferably 20-25°C. till the pH is 4-7 preferably 6-7.
c) further extraction of the aqueous layer of the resultant biphasic system with halogenated soh ents selected from methylene chloride or ethylene chloride preferably methylene chloride;
d) combining the organic layers and subjecting to carbon treatment accompanied by distillation;
e) addirion of ketone solvent selected from acetone or CrC^ alcohols preferably isopropyl alcohol and filtering the resultant solid of formula (3);
J
0 reading Rosiglitazone of formula 3 with maleic acid in ketone solvent selected from acetone or halogenated solvent selected from chlorofomi or methylene chloride preferably acetone, at tteir respective reflux temperatures for a period of 15 minutes to 2 hours preferably 20-30 minutes;
g) subjecting the clear solution obtained in step f) to carbon treatment;
h) filtering and optionally distilling the solvent to dryness;
i) in case of optional distillation, adding ketone solvent selected from acetone or halogenated solvent selected from chloroform or methylene chloride preferably acetone;
j) stirring the reaction mixture of step i) at a temperature in the range of 0-40*^0
preferably 6-20°C for a period of 15 minutes to 2 hours preferably 20 - 30 minutes and
k) isolating the Rosiglitazole maleate salt of Formula (1) by conventional methods.
2. A process according to claim lof step (a), wherein the cobalt ion source is cobalt chloride Hexahydrate.
3. A process according to claim 1 of step (a), wherein the said ligand is dimethyl glyoxime.
4. A process according to claim 1 of step (a), wherein the reducing agent is sodiumborohydride.
5. An improved process for the preparation of Rosiglitazone maleate herein described with particular reference to example.