Filed of the Invention:
The present invention relates to a novel salt of rosiglitazone, namely rosiglitazone succinate compound of formula-1 and its hydrates, solvates, polymorphs as well as a process for its preparation. The present invention also provides a process for the preparation of rosiglitazone compound of formula-2. Rosiglitazone is chemically known
as (±)-5-[[4-[2-(methyl-2pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione, represented by the following structure

Rosiglitazone is a member of the thiazolidinedione class of compounds and is particularly useful for the treatment of Type 11 diabetes. Rosiglitazone is commercially available as its maleate salt under the brand name of Avandia®.
Background of the Invention:
Rosiglitazone and process for its preparation was first disclosed in US 5002953. As per the disclosed process rosiglitazone is prepared from 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene]thijizolidine-2,4-dione by catalytic reduction i.e., in presence of palladium on carbon. The said patent also disclosed the melting point of both compounds. The said patent has not exemplified the salts of rosiglitazone.

us 5741803 disclosed the certain salts of rosiglitazone and the preferred is maleic acid salt of rosiglitazone. WO 02/12232 disclosed the DL tartarate salt of rosiglitazone. WO 02/20519 disclosed the hydrochloride salt of rosiglitazone. WO 05/023803 disclosed the phosphate salt of rosiglitazone. These salts have substantial water solubility, but the dissolution profiles are not quite satisfactory. Hence there is need in the art for new salt of rosiglitazone, with proper dissolution profiles.
US 7435741 disclosed the succinic acid derivative of rosiglitazone, as an impurity formed by the reaction of rosiglitazone with maleate, during the preparation of rosiglitazone maleate salt. But the said application no where discloses the possibility for the formation of succinic acid salt of rosiglitazone. Hitherto succinic acid salt of rosiglitazone has not been reported in the literature.
Surprisingly the present inventor prepared the succinic acid salt of rosiglitazone and found that it has advantageous physical properties over the known salts of rosiglitazone. The succinic acid salt of the present invention is stable, high melting crystalline material and hence suitable for bulk preparation and handling. The succinic acid salt is amenable to large scale pharmaceutical processing, especially in the manufacturing processes which require or generate heat, for example milling, drying in different types of vacuum driers, spray drying and sterilization by autoclaving etc.
This novel sah can be prepared by efficient and economic process reproducible on a commercial scale. Accordingly the present invention provides the novel succinic acid salt of rosiglitazone, polymorphs and process for their preparation
Brief Description of the Invention:
The first aspect of the present invention is to provide a novel sah of rosiglitazone, namely rosiglitazone succinate compound of formula-1. The present invention also relates to its solvates and hydrated forms.
The second aspect of the present invention is to provide a process for the preparation of novel rosiglitazone succinate.

The third aspect of the present invention is to provide the polymorphic form of rosiglitazone succinate compound of formula-1. The novel form of the present invention is characterized by its PXRD, IR and DSC theromogram.
The fourth aspect of the present invention is to provide an improved process for the preparation of rosiglitazone compound of formula-2, which comprises of reducing the 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene]thiazolidine-2,4-dione compound of formula-9 by hydrogenation in presence of a suitable catalyst in a suitable solvent.
The fifth aspect of the present invention is to provide an improved process for the preparation of rosiglitazone compound of formula-2.
The sixth aspect of the present invention is to provide one pot process for the preparation of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene]thiazolidine-2,4-dione compound of formula-9.
The seventh aspect of the present invention is to provide an improved process for the preparation of rosiglitazone compoimd of formula-2, which comprises of reducing the 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene]thiazolidine-2,4-dione compound of formula-9 in presence of cobalt ion, a ligand and a reducing agent.
Brief Description of the Drawings:
Figure-l: Illustrates the PXRD of rosiglitazone succinate of the present invention
Figure-2: Illustrates the IR spectrum of rosigliazone succinate of the present invention
Figure-3: Illustrates the DSC thermogram of succinate of the present invention
Figure-4: Illustrates the PXRD of rosiglitazone compound of formula-2 prepared as per
the process disclosed in US 5002953.
Figure-5: Illustrates the PXRD of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]
benzylidene]thiazolidine-2,4-dione compound of formula-9 prepared as per the process
disclosed in US 5002953.

Detailed Description of tlie Drawings:
The present invention relates to novel salt of rosiglitazone, its polymorphic form and process for their preparations.
Accordingly, the first aspect of the present invention provides novel rosiglitazone succinate compound of formula-1 having the following structural formula

and its hydrates and solvates thereof
The novel rosiglitazone succinate of the present invention exists in either crystalline or amorphous form. The rosiglitazone succinate of the present invention is stable, high melting, free flowing crj^stalline material, easy to handle and hence suitable for bulk preparation. The novel rosiglitazone succinate salt of the present invention used as an active pharmaceutical ingredient in pharmaceutical composition.
The present invention also provides a process for the preparation of rosiglitazone succinate compound of formula-1, which comprises of reacting the rosiglitazone compound of formula-2 with succinic acid in a suitable solvent selected from alcoholic solvents like methanol, ethanol, isopropanol, n-propanol and butanol; ester solvents like ethylacetate, methyl acetate, isopropylaceatate, ketone solvents like acetone, methyl isobutyl ketone; nitrile solvents like acetonitrile, hydrocarbon solvents like toluene, xylene, heptane, cyclohexane, hexeme and their mixtures thereof; to provide the rosiglitazone succinate.
The second aspect of the present invention provides novel crystalline form of rosiglitazone succinate, compound of formula-1. The novel crystalline form of the present invention is herein designated as "Form-M". The crystalline form-M of the present invention is characterized by its powder X-ray diffractogram having characteristic

peaks at 13.53,13.93, 16.63, 17.30,19.96,20.23,22.05,23.63, 25.33,26.09, 31.44, 35.33 and 38.20 ± 0.2 degree 26 and the same has been represented in figure-l. It is also characterized by its Infra-Red spectrum with characteristic peaks at 2931.87, 2651.02, 1694.07, 1609.07, 1509.12, 1475.13, 1427.96, 1313.13, 1246.68, 1203.14, 1171.58, 1110.95,1076.20, 970.04,920.04, 831.00, 719.05, 662.95, 587.02 and 529.84 cm"' which is represented in figure-2 and it is also characterized by its Differential Scanning Calorimetry thermogram having endothermic peak at 127.27°C as shown in figure 3.
The third aspect of the present invention provides a process for the preparation novel crystalline Form-M of rosiglitazone succinate compound of formula-1, which comprises of treating the rosiglitazone compound of formula-2 with succinic acid in methanol, followed by removal of methanol by distillation to provide the crystalline form M of rosiglitazone succinate compound of formula-1.
The present invention also provides alternate process for the preparation of novel crystalline Form-M of rosiglitazone succinate, compound of formula-1 by treating rosiglitazone compound of formula-2 with succinic acid in a suitable alcoholic solvent and finally isolating the crystalline form-M from a suitable hydrocarbon solvent like toluene, xylene, heptane, cyclohexane, hexane and their mixtures thereof; preferably cyclohexane.
The fourth aspect of the present invention provides an improved process for the preparation of rosiglitazone compoimd of formula-2, which comprises reducing the 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy] benzylidene]thiazolidine-2,4-dione compound offormula-9


by hydrogenation in presence of a suitable catalyst like palladium/carbon, in a suitable solvent selected from methanol, ethiinol, isopropanol, n-propanol or mixtures thereof at a temperature ranges from 25 to 90°C, preferably at 75-80°C.
The fifth aspect of the present invention provides an improved process for the preparation of rosiglitazone compound of formula-2 comprising of, a) reacting 2-chloropyridine, compoimd of formula-3

in the presence of a base in a suitable solvent provides 4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzaldehyde compoimd of formula-7.


c) which on in-situ reaction with 2,4-thiazolidinedione, compound of formula-S

in a suitable solvent and in presence of piperidinium acetate provides 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene]thiazolidine-2,4-dione compound of formuia-9,

d) 5-[4-[2-(N-methyl-N-(2-pyridyl)ajtnino)ethoxy]benzylidene]thiazolidine-2,4-dione
compound of formula-9 on hydrogenation in presence of a suitable catalyst like
Palladium/Carbon in a suitable solvent selected from methanol, ethanol, isopropanol,
n-propanol, n-butanol or mixtures thereof, at a temperature ranges from 25 to 90°C,
preferably at 75-80°C provides rosiglitazone compound of formula-2.


In the fifth aspect of the present invention,
In step b) the base is selected from the group consisting of but is not limited to,
alkali metal/ alkaline earth metal hydroxides such as sodium hydroxide, potassium
hydroxide, calcimn hydroxide, magnesium hydroxide, and lithium hydroxide; alkali
metal/ alkaline earth metal carbonates such as potassium carbonate, sodium carbonate,
lithium carbonate and cesium carbonate preferably potassium carbonate and the suitable
solvent is selected from The suitable solvent which is used is selected from a group
which includes but is not limited to benzene, toluene, xylene, tetrahydofliran, 2-
methyltetrahydroftiran, ethylene glycol, dimethylformamide, dimethylsulfoxide, tetrahydrofuran., preferably dimethylformamide
In the step c) the suitable solvent is selected from alcoholic solvents like methanol, ethanol, isopropanol, n-propanol, n-butanol or the mixtures thereof, preferably methanol
In the step d) the suitable solvent is selected from alcoholic solvents like methanol, ethanol, isopropanol, n-propanol, n- butanol or mixtures thereof, preferably methanol.
The sixth aspect of the present invention provides one pot process for the preparation of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene]thiazolidine-2,4-dione compovind of formula-9 which comprises of



Formula-7 c) which on in-situ reacting with 2,4-thiazolidinedione, compound of formula-S

in a suitable solvent, in presence of piperidinium acetate provides 5-[4-[2-(N-methyl-N-(2-pyridyl)ainino)ethoxy]benzylidene]thiazolidine-2,4-dione compound of fonnula-9.


The seventh aspect of the present invention provides an improved process for the preparation of rosiglitazone compound of formula-2, which comprise of reducing the 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene]thiazolidine-2,4-dione compound of formula-9 in presence of cobalt ion, a ligand and a reducing agent.
The cobalt ion used in the above process is selected from the group which comprises of but is not limited to cobaltous chloride, cobaltous diacetate, cobaltic chloride and the like; and the ligand is selected from the group consisting of dimethylglyoxime, 2,2'-bipyridyl and 1,10-phenathroline; the reducing agent is like vitride.
The present invention is schematically represented by the following scheme-1 & 2
Scheme-1:
r ^,. 1


The 5-[4-[2-(N-inethyl-N-(2-pyridyl)ainino)ethoxy] benzylidene]thiazolidine-2,4-dione compound of formula-9 was prepared as per the process disclosed in US 5002953. The said patent disclosed formula-9 as a crystalline solid with the melting point of 177-179°C. The PXRD of compound of formula-9 prepared as per example-31 of US 5002953 is shown in figure-5.
US 5002953 also disclosed the rosiglitazone as a crystalline solid with the melting point of 153-155°C. The PXRD of rosiglitazone prepared as per the process disclosed in example-30 of the US 5002953 is shown in figure-4. The PXRD of rosiglitazone prepared as per the present invention is similar to the PXRD shown in figure-4.
XRD analysis of Rosiglitai^one, its intermediates and its pharmaceutically acceptable sahs were carried out using SIEMENS/D-5000 X-Ray diffractometer using Cu, Ka radiation of wavelength 1.54 A° and continuous scan speed of 0.0457min. FI-IR spectrum of rosiglitazone sucicnate v/as recorded on Thermo model Nicolet-380 as KBr pellet. The thermal analysis of rosiglitazone succinate was carried out on Waters DSC Q-10 model differential scanning calorimeter.

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration purpose only and therefore should not be construed as limitation of the scope of the present invention.
Examples:
Example-1: Preparation of rosiglitazone compound of formula-2:
Palladium carbon (40 grams) was added to a mixture of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene]thiazolidine-2,4-dione (compound of formula-2) (100 grams), sodium hydroxide solution (240 ml) and aqueous methanol (400 ml in 1400 ml of water) at 25-30°C. The reaction mixture was stirred for 30 minutes and hydrogen gas was applied. The reaction mixture was heated to 75-80°C and stirred xintil the reaction was complete. The reaction mixture was cooled to room temperature and treated with carbon. The reaction mixture was filtered through hyflow. The filtrate was acidified with acetic acid and stirred for 2 hours at 25-3 0°C to precipitate a solid. Ethyl acetate (300 ml) was added to the reaction mixture, stirred for 30 minutes. The obtained solid was filtered, washed with water. Methanol (200 ml) was added to the obtained solid, and refluxed for 1 hour, then cooled to 25-3 0°C and stirred for 2 hours. The obtained solid was filtered, washed with methanol and dried to get the title compound. Yield: 78 grams
Example-2: Preparation of rosiglitazone compound of formula-2:
To the mixture of cobalt(II) chloride(1.9 g) in water (2200 ml) added 4% sodium hydroxide solution (6g in 144ml of water), dimethyl glyoxime (1.9g) and tetrahydrofiiran (730 ml). To this reaction mixture added 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy] benzylidene]thiazolidine-2,4-dione compound of formula-2 (100 g) and vitride (68 g). Stirred the reaction mixture for 10 hrs. The reaction mixture was quenched with dilute hydrochloric acid and the precipitated solid was filtered. Dried the material to get the title compound. Yield: 75 grams

ExanipIe-3: Preparation of rosiglitazone compound of formula-2:
Palladium carbon (40 grams) was added to a mixture of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene]thia2olidine-2,4-dione (compound of formula-2) (100 grams),sodium hydroxide solution (240 ml) and aqueous methanol (400 ml in 1400 ml of water) at 25-30°C. Hydrogen gas was applied to the reaction mixture and stirred up to the completion of reaction at 25-30°C. The reaction mixture was subjected to carbon treatment and filtered through hyflow. The filtrate was acidified with acetic acid and stirred for 2 hours at 25-30°C, solid formed. Ethyl acetate (300 ml) was added to the reaction mixture, stirred for 30 minutes. The obtained solid was filtered, washed with water. Methanol (200 ml) was added to the obtained solid and stirred for 1 hour at reflux temperature. The reaction mixture was cooled to 25-3 0°C, stirred for 2 hours. The obtained solid was filtered, washed with methanol and dried to get the title compound. Yield: 70 grams
Example-4: Preparation of rosiglitazone succinate compound of formula-1:
A mixture of rosiglitazone (100 grams), succinic acid (36 grams) and methanol (3500 ml) was heated to 60-65°C. The reaction mixture was treated with carbon and stirred for 30 minutes at 60-65°C. The reaction mixture was filtered. The solvent fi-om the filtrate was completely distilled off under reduced pressure to get the title compound as a crystalline solid. Yield: 90 grams
Example-5: Preparation of crystalline form-M of rosiglitazone succinate compound of formula-1:
Rosiglitazone (100 grams) £ind succinic acid (36 grams) was dissolved in methanol (3500 ml) at 60-65°C. The reaction mixture was subjected to carbon treatment, stirred for 30 minutes at 60-65°C and filtered through hyflow. The filtrate was distilled off under reduced pressure at 50-60°C. Cyclohexane was added to the residue and distilled off completely under reduced pressure. Cyclohexane was added to the residue and then the reaction mixture was cooled to room temperature. The reaction mixture was seeded with standard rosiglitazone succinate and stirred for 2 hous at 0-5°C. The solid was filtered, washed with cyclohexane and dried to get the title compound Yield: 115 grams
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ExampIe-6: Preparation of crystalline form-M of rosiglitazone succinate compound of formula-1:
Rosiglitazone (100 grams) and succinic acid (36 grams) was dissolved in methanol (3500 ml) at 60-65°C. The reaction mixture was subjected to carbon treatement and then filtered through hyflow. The solvent from the filtrate was distilled off completely under reduced pressure at 60-65 °C to get the title compound. Yield: 110 grams.
Example-7: Preparation of rosiglitazone compound of formula-2:
Rosiglitazone succinate (100 grams) was dissolved in ethyl acetate (500 ml) and aqueous potassium carbonate (58 g) was added to it. Stirred the reaction mixture. Separated the organic layer and washed with water. Distilled off the solvent completely from the organic layer. Filtered the obtained solid and dried to get the title compound. Yield: 70 grams.
ExampIe-8: Preparation of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy] benzylidene]thiazolidine-2,4-dione compound of formula-9:
A mixture of 2-chloropyridine (50 grams) and 2-methyl amino ethanol (82.6 grams) was heated to 120-125°C and stirred for 25 hours. The reaction mixture was cooled to room temperature water (100 ml) and toluene (100 ml) was added to it. The aqueous and organic layers were separated and an aqueous layer was extracted with toluene. The organic layers were combined and the solvent was distilled off completely to provide a residue. To this residue added dimethylformamide (1500 ml), potassium carbonate (150.7 g) and 4-fluoro benzaldehyde compound of formula-6 (85 g) and stirred the reaction mixture for 10 hrs at 25°-30°C. Added water (2500 ml) to the reaction mixture and stirred for 10 hours. Filtered the solid obtained. To the wet compound added 2,4 thiazolidine dione (55 g), piperidine(5 g) and acetic acid (2.76g). Stirred the reaction mixture for 6 hours at azeotropic reflux temperature. Cooled the reaction mixture to 25-30°C to obtain a solid, which was filtered and dried to get the title compound as a solid. Yield: 125 grams
-15

Example-9: Preparation of 4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxyJ benzaldehyde Compound of formulla-7:
To 2-(N-methyl-N-(2-pyridyl)amino)ethanol, compound of formula-5 (100 g) taken in dimethylformamide (1000 ml) added potassium hydroxide (184 g), 4-fluoro benzaldehyde (compound of formula-6) (119.7 g) and stirred the reaction mixture for 16 hrs at 50°-55°C. Water (500 ml) to the reaction mixture and stirred for 15 minutes. Cooled the reaction mixture to 30°C, filtered the solid obtained and dried to get the title compound. Yield: 155 grams.
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1. Succinic acid salt of rosiglitazone compound having the following structural
Formula-1

2. Crystalline rosiglitazone succinate compound of formula-1.
3. Crystalline form-M of rosiglita2:one succinate compound of formula-1 characterized by any one of the following,

(a) its powder X-ray difractogram having characteristic 29 peaks at 13.53, 13.93, 16.63, 17.30, 19.96, 20.23, 22.05, 23.63, 25.33, 26.09, 31.44, 35.33 and 38.20 ± 0.2 degrees of two theta
(b) its IR wherein peaks were observed at 2931.87, 2651.02, 1694.07, 1609.07, 1509.12, 1475.13, 1427.96, 1313.13, 1246.68, 12.3.14, 1171.58, 1110.95, 1076.20, 970.04, 920.04, 831.00, 719.05, 662.95, 587.02 and 529.84 cm-1
(c) its DSC thermogram having endothermic peak at about 127.27°C.

4. A process for the preparation of rosiglitazone succinate comprises of treating the rosiglitazone with succinic acid in a suitable solvent followed by removal of solvent by distillation to provide the rosiglitazone succinate compound of formula-la.
5. The process as claimed in claim 4, wherein the suitable solvent for the preparation of rosiglitazone succinate is selected from water; alcoholic solvents like methanol, ethanol, isopropanol, n-propanol and butanol; ester solvents like ethylacetate, methyl acetate, isopropylaceatate, ketone solvent like acetone, methyl isobutyl ketone; nitrile solvents like acetonitrile, hydrocarbon solvents like toluene, heptane, cyclohexane and hexane, and their mixtures thereof.

6. A process for the preparation of rosiglitazone succinate comprises of treating the rosiglitazone with succinic acid in methanol followed by removal of methanol by distillation to provide the rosiglitazone succinate compoimd of formula-1.
7. A process for the preparation of crystalline form-M of rosiglitazone succinate comprising of;
i) suspending rosiglitazone succinate in a suitable solvent selected from water; alcoholic solvents like methiinol, ethanol, isopropanol, n-propanol and butanol; ester solvents like ethylacetate, methyl acetate, isopropylaceatate, ketone solvent like acetone, methyl isobutyl ketone; nitrile solvents like acetonitrile, hydrocarbon solvents like toluene, heptane, cyclohexane and hexane, and their mixtures thereof,
ii) isolating crystalline form-M of rosiglitazone succinate.
8. The process as claimed in claim 7, wherein the suitable solvent used for the preparation of Rosiglitazone succinate is selected from water; alcoholic solvents like methanol, ethanol, isopropanol, n-propanol and butanol; ester solvents like ethylacetate, methyl acetate, isopropylaceatate, ketone solvent like acetone, methyl isobutyl ketone; nitrile solvents like acetonitrile, hydrocarbon solvents like toluene, heptane, cyclohexane and hexane, and their mixtures thereof.
9. One pot process for ithe preparation of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene]thiazolidine-2,4-dione compound of formula-2,


Formula-3 with 2-(N-methylamino)ethanol, compound of fomiula-4

in the absence of solvent to provide 2-(N-methyl-N-(2-pyridyl)aniino)ethanol compound of formula-5,

b) which on in-situ reaction with 4-fluoro benzaldehyde compound of formula-6

in the presence of a base in a suitable solvent provides 4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzaldehyde compound of formula-7,

c) which on in-situ reaction with 2,4-thiazolidinedione, compound of formula-8


in a suitable solvent, in presence of piperidinium acetate provides 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene]thiazolidine-2,4-dione compound of formula-9.
10. Usage of Rosiglitazone succinate in the preparation of highly pure Rosiglitazone compound of formula-2 as well as active ingredient in the preparation of pharmaceutical composition.

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