DESC:RELATED PATENT APPLICATION:

This application claims the priority to and benefit of Indian Patent Application No. 202241041165 filed on July 19, 2022; the disclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION:

The present invention relates to a process for the preparation of Lobeglitazone (compound of formula I) or its pharmaceutically acceptable salts thereof. More particularly the present invention relates to a novel process for preparation of the intermediate 4-(2-{[6-(4-methoxyphenoxy)pyrimidin-4-yl]methylamino}ethoxy)benzaldehyde (compound of formula III) and its use in the preparation of Lobeglitazone or its pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION:

Lobeglitazone is chemical known as 5-[[4-[2-[[6-(4-methoxyphenoxy)-4-pyrimidinyl]-methylamino]-ethoxy]phenyl]methyl]-2,4-thiazolidinedione and has the structural formula as mentioned below:

Lobeglitazone is marketed as a sulfate salt in the name “Duvie” in Korea as an anti-diabetic medication and used for oral administration as a tablet.

The US Patent 6787551, assigned to Chong Kun Dang Pharma discloses Lobeglitazone and a process for preparing the same as mentioned below:

The O-arylation of 2-[6-(4-methoxyphenoxy)pyrimidin-4-yl]methylaminoethanol with 4-flurobenzaldehyde in the aforementioned process, yields the desired product 4-(2-{[6-(4-methoxyphenoxy)pyrimidin-4-yl]methylamino}ethoxy)benzaldehyde of about 80%, rest are undesired products that should be removed before proceeding to the next stage of the reaction and the same was discussed in the Publication Journal Organic Process Research & Development 2007, 11, pages 190-199.

The structure of impurities formed during the process for the preparation of Lobeglitazone as disclosed in the US Patent 6787551 are mentioned below:

The Publication Journal Organic Process Research & Development 2007, 11, pages 190-199 disclose the reduction in the formation of undesired product by the use of sodium hydroxide or potassium hydroxide during the reaction instead of sodium hydride and potassium fluoride.

Hence, there is a need to develop a novel process for the preparation of Lobeglitazone or its pharmaceutically acceptable salts thereof overcoming the drawbacks of the prior arts.

OBJECTS OF THE INVENTION:

The primary object of the present invention is to provide a novel process for the preparation of Lobeglitazone.

Another object of the present invention is to provide a novel process for preparation of Lobeglitazone and its pharmaceutically acceptable salts thereof using an intermediate of formula III.

Yet another object of the present invention is to provide a novel process for the preparation of said intermediate of formula III.
SUMMARY OF THE INVENTION:

Accordingly, the present invention provides a novel process for the preparation of Lobeglitazone and its salts thereof using an intermediate of formula III. The present invention also provides a process for the preparation of the intermediate of formula III.

The primary aspect of the present invention is to provide a process for preparing Lobeglitazone or its pharmaceutically acceptable salts thereof, comprising the steps of:
(i) reacting a compound of formula V as mentioned below,

with 4-hydroxybenzaldehyde in presence of a solvent to obtain a compound of formula IV as mentioned below,

wherein PG is an amino protecting group and R is a halogen group or a hydroxy group;

(ii) reacting the compound of formula IV with a compound of formula VIII, as mentioned below, in presence of a solvent,

to obtain a compound of formula III as mentioned below,

wherein X is a halogen group;

(iii) condensing the compound of formula III with thiazolidinone in presence of a solvent to obtain a compound of formula II as mentioned below;

(iv) reducing the compound of formula II in presence of a solvent to obtain Lobeglitazone of formula I; and

(v) optionally converting Lobeglitazone into its pharmaceutically acceptable salts thereof.

The PG group of the compound of formula V in step (i) of said process is selected from the amino protecting group comprising of carbobenzyloxy group, p-methoxybenzyl carbonyl group, tert-butyloxy-carbonyl group, 9-fluorenylmethyloxycarbonyl group, acetyl group, benzoyl group, benzyl group, carbamate group, p-methoxyphenyl group, and tosyl group.

The R group of the compound of formula V in step (i) of said process is selected from halogen group comprising of chloro, bromo, fluoro and iodo.

In the said process, the X group of the compound of formula VIII in step (ii) is selected from halogen group comprising of chloro, bromo, fluoro and iodo.

The solvent in step (i) of said process is selected from polar organic solvent comprising of alcohol selected from ethanol, methanol, or isopropanol; ketone selected from acetone or methyl isobutyl ketone; acetonitrile; dimethylformamide; dimethylsulfoxide; aromatic hydrocarbon selected from toluene or benzene; aliphatic hydrocarbon selected from hexane or heptane; and mixtures thereof.

The solvent in step (ii) of said process is selected from polar organic solvent comprising of alcohols selected from ethanol, methanol, or isopropanol; ketone selected from acetone or methyl isobutyl ketone; acetonitrile; dimethylformamide; dimethylsulfoxide; and mixtures thereof.

The solvent in step (iii) of said process is selected from organic solvent comprising of aliphatic hydrocarbons selected from hexane or heptane; aromatic hydrocarbons selected from toluene or benzene; chlorinated hydrocarbons selected from dichloromethane or chloroform; alcohol selected from ethanol or methanol; and mixtures thereof.

The condensation process in step (iii) of said process employs piperidine, piperidinium acetate or benzoate.

The reduction process in step (iv) of said process employs sodium borohydride or lithium borohydride or palladium.

The solvent in step (iv) of said process is selected from the group comprising of dimethylformamide; alcohol selected from ethanol or methanol; ethers selected from dioxane or tetrahydrofuran; ethyl acetate; aromatic hydrocarbon selected from benzene or toluene; and mixtures thereof.

The reduction process in step (iv) of said process employs Hantzsch ester.

In the present invention, the pharmaceutically acceptable salt of Lobeglitazone is Lobeglitazone sulfate.

Another aspect of the present invention is to provide a process for preparing a compound of formula III, comprising the steps of:
(i) reacting a compound of formula V as mentioned below,

with 4-hydroxybenzaldehyde in presence of a solvent to obtain a compound of formula IV as mentioned below,

wherein PG is an amino protecting group and R is a halogen group or a hydroxy group; and
(ii) reacting the compound of formula IV with a compound of formula VIII in presence of a solvent as mentioned below,

to obtain a compound of formula III as mentioned below,

wherein X is a halogen group.

The PG group of the compound of formula V in step (i) of said process is selected from the amino protecting group comprising of carbobenzyloxy group, p-methoxybenzyl carbonyl group, tert-butyloxy-carbonyl group, 9-fluorenylmethyloxycarbonyl group, acetyl group, benzoyl group, benzyl group, carbamate group, p-methoxyphenyl group, and tosyl group.

The R group of the compound of formula V in step (i) of said process is selected from halogen group comprising of chloro, bromo, fluoro and iodo.

In the said process, the X group of the compound of formula VIII in step (ii) is selected from halogen group comprising of chloro, bromo, fluoro and iodo.

The solvent in step (i) of said process is selected from polar organic solvent comprising of alcohol selected from ethanol, methanol, or isopropanol; ketone selected from acetone or methyl isobutyl ketone; acetonitrile; dimethylformamide; dimethylsulfoxide; aromatic hydrocarbon selected from toluene or benzene; aliphatic hydrocarbon selected from hexane or heptane; and mixtures thereof.

The solvent in step (ii) of said process is selected from polar organic solvent comprising of alcohols selected from ethanol, methanol, or isopropanol; ketone selected from acetone or methyl isobutyl ketone; acetonitrile; dimethylformamide; dimethylsulfoxide; and mixtures thereof.

DETAILED DESCRIPTION OF THE INVENTION:

Accordingly, in one aspect the present invention discloses and describes a novel process for the preparation of Lobeglitazone and its salts thereof.

A process for preparing Lobeglitazone or its pharmaceutically acceptable salts thereof, comprising the steps of:
(i) reacting the compound of formula V as mentioned below,

with 4-hydroxybenzaldehyde to obtain a compound of formula IV as mentioned below,

wherein PG is any amino protecting group and R is any halogen group or a hydroxy group;

(ii) reacting the compound of formula IV with a compound of formula VIII as mentioned below,

to obtain the compound of formula III as mentioned below,

wherein X is any halogen group;

(iii) condensing the compound of formula III with thiazolindinone to obtain the compound of formula II as mentioned below,

(iv) reducing the compound of formula II to obtain Lobeglitazone of formula I;

(v) optionally converting Lobeglitazone into its pharmaceutically acceptable salts thereof.

The “PG” group denoted in the compound of formula V of step (i) of the present process herein refers to any amino protecting group selected from but not limited to carbobenzyloxy group; p-methoxybenzyl carbonyl group; tert-butyloxy-carbonyl group; 9-fluorenylmethyloxycarbonyl group; acetyl group; benzoyl group; benzyl group; carbamate group; p-methoxyphenyl group; or tosyl group.

The “R” denoted in the compound of formula V of step (i) of the present process is any halogen group or a hydroxy group; wherein the halogen group is independent of each other and includes chloro, bromo, fluoro and iodo group.

The “X” group denoted in the compound of formula VIII of step (ii) of the present process herein refers to any halogen group independent of each other and includes chloro, bromo, fluoro and iodo groups.

The step of reacting the compound of formula V with 4-hydroxybenzaldehyde according to the step (i) of the present invention, is carried out in the suitable solvents selected from but not limited to the polar organic solvents comprising of group of alcohols such as ethanol, methanol or isopropanol; ketone such as acetone or methyl isobutyl ketone; nitrile such as acetonitrile; amides such as dimethylformamide; dimethylsulfoxide; aromatic hydrocarbon such as toluene or benzene; aliphatic hydrocarbon such as hexane or heptane or its mixtures thereof.

The step of reacting the compound of formula V with 4-hydroxybenzaldehyde according to the step (i) of the present invention, may be carried out in the range from ambient temperature to reflux temperature of solvent or its mixture used during the reaction.

The step of reacting the compound of formula IV with a compound of formula VIII according to the step (ii) of the present invention, is carried out in polar organic solvents selected from but not limited to the group of alcohols such as ethanol, methanol, or isopropanol; ketone such as acetone or methyl isobutyl ketone; nitrile such as acetonitrile; amides such as dimethylformamide; dimethylsulfoxide; or its mixtures thereof.

The step of condensing the compound of formula III with thiazolindinone according to the step (iii) of the present invention, is carried out in organic solvents selected from but not limited to the group comprising of: aliphatic hydrocarbons such as hexane and heptane; aromatic hydrocarbons such as toluene and benzene; chlorinated hydrocarbons such as dichloromethane and chloroform; alcohol such as ethanol or methanol; or its mixtures thereof.

Preferably the step of condensing the compound of formula III with thiazolindinone according to the step (iii) of the present invention, may be carried out in the presence of piperidine, piperidinium acetate or benzoate.

Preferably the step of reducing the compound of formula II to obtain Lobeglitazone of formula I according to the step (iv) of the present invention, may be carried out in the presence of sodium borohydride or lithium borohydride or palladium on carbon in a suitable solvent selected from the group comprising of dimethylformamide; alcohol such as ethanol and methanol; ethers such as dioxane and tetrahydrofuran; esters such as ethyl acetate; aromatic hydrocarbon such as benzene or toluene; or its mixtures thereof.

The step of reducing the compound of formula II to obtain Lobeglitazone of formula I according to the step (iv) of the present invention, may also be carried in the presence of Hantzsch ester.

The compound of formula V used in the step (i) of the present invention as mentioned below,

may be prepared from the N-methyl-aminoethanol by the process as mentioned below:

Surprisingly, the process of the present invention avoids the drawbacks of the process for preparing Lobeglitazone as disclosed in the prior arts.

In another aspect the present invention discloses a process for the preparation of an intermediate compound of formula III.

A process for preparing the compound of formula III, comprising the steps of:
(i) reacting the compound of formula V

with 4-hydroxybenzaldehyde to obtain a compound of formula IV as mentioned below,

wherein PG is any amino protecting group and R is any halogen group or a hydroxy group; and

(ii) reacting the compound of formula IV with a compound of formula VIII as mentioned below,

to obtain the compound of formula III as mentioned below,

wherein X is any halogen group.

The schematic representation of the process disclosed in the present invention is mentioned below in Scheme-I and Scheme-II.

Certain specific aspects and embodiments of the present invention will be explained in detail with reference to the following examples described below, which are given for the purpose of illustration only and are not intended to limit the scope of the invention.

EXAMPLES

Example-1: Preparation of the 4-(4-methoxy)phenoxy-6-chloropyrimidine (Compound of formula-VIII, wherein X is chloro)

To a solution of 4,6-dichloropyrimidine (20 gm) in anhydrous dimethylformamide (160 ml), potassium fluoride (23.4 gm) was added followed by the addition of p-methoxyphenol (16.6 gm) at 30-35°C. The reaction mixture was then heated to 80°C and stirred at the same temperature for 4-5 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was quenched in water (100 ml) and the product in the reaction mass was extracted with ethyl acetate (600 ml). The extracted ethyl acetate layer was concentrated under vacuum to obtain a residue.
Yield: 30 gm; % Yield: 95%.

Example-2: Preparation of N-methyl-2-chloro-ethanamine hydrochloride

To a cooled solution of 2-methylaminoethanol (10 gm) in dichloromethane (100 ml), thionyl chloride solution (13 ml of thionyl chloride in 20 ml of dichloromethane) was added at 5-10°C for 25 minutes and stirred at 30-35°C for 10-12 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was concentrated under vacuum to obtain a residue.
Yield: 15.5 gm; % Yield: 89%.

Example-3: Preparation of tert-butyl(2-chloroethyl)-N-methyl-carbamate (Compound of formula-V, wherein PG is BoC group and X is chloro)

To a solution of N-methyl-2-chloro-ethanamine hydrochloride (10 gm) in dichloromethane (100 ml), triethylamine solution (23.43 gm of triethylamine in 10 ml of dichloromethane) was added at 0-10°C followed by the addition of Boc-anhydride solution (20.21 gm of Boc anhydride in 5 ml of dichloromethane) for 20 minutes at 0-10°C. The reaction mixture was then stirred at 30-35°C for 10-12 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was diluted with water (100 ml) and the product in the reaction mass was extracted with dichloromethane (2 x 100 ml). The combined dichloromethane extracts were dried over sodium sulphate; and concentrated under vacuum to obtain a residue.
Yield: 9.2 gm; % Yield: 62%.

Example-4: Preparation of 4-[2-(N-methyl-amino)ethanoxy]-benzaldehyde (Compound of formula-IV)

To a solution of 4-hydroxybenzaldehyde (5.0 gm) in N, N-dimethylformamide (50 ml), tert-butyl-(2-chloroethyl)-N-methyl-carbamate (9.0 gm), potassium carbonate (19.23 gm), and a catalytic amount of tetrabutylammonium bromide (1 mg) were added and stirred at 30-35°C for 2 hours. The reaction mixture was then heated to 80? and maintained for 8 hours at the same temperature. The progress of the reaction was completed by TLC. After completion of the reaction, water (300 ml) and toluene (150 ml) were added to the reaction mass to obtain a biphasic mixture. The organic layer was separated; washed with water; and concentrated under vacuum to obtain a residue. The obtained residue was dissolved in the hydrochloride in ethyl acetate solution (50 ml, 10%) and stirred for 10 hours at 30-35°C. The progress of this deprotection reaction was monitored by TLC. After completion of the deprotection reaction, the reaction mass was concentrated under vacuum to obtain a residue. The residue was dissolved in water and the pH of the solution was adjusted to 10.0-11.0 by adding aqueous 10% sodium hydroxide solution and stirred for 2 hours at 30-35°C for deprotection. Ethyl acetate (50 ml) was added to the prepared solution and stirred for 15 minutes to form a biphasic mixture. The organic layer was separated and concentrated under vacuum to obtain a residue.
Yield: 1.7 gm; % Yield: 37%.

Example-5: Preparation of 4-[2-(N-tert-butyoxycarbonyl-N-methyl-amino)-ethanoxy]-benzaldehyde

To a solution of 4-hydroxybenzaldehyde (2 gm) in tetrahydrofuran (25 ml), diisopropyl azodicarboxylate (DIAD) (4.32 gm) was added at 0°C, followed by the addition of tert-butyl-(2-hydroxyethyl)-N-methyl-carbamate (3 gm) and triphenyl phosphine (5 gm) at 0°C. The reaction mixture was then stirred for 20 hours at 30-35?. The progress of the reaction was monitored by TLC. After the completion of the reaction, water (20 mL) was added to the reaction mass and the product in the reaction mass was extracted with dichloromethane (2 x 100 ml). The combined dichloromethane extracts were washed with water, dried over sodium sulfate, filtered, and concentrated under vacuum to obtain a residue. Yield: 3.0 gm; % Yield: 94%.

Example-6: Preparation of Compound of formula-III

To a solution of 4-[2-(N-methyl-amino)ethanoxy]-benzaldehyde (1.0 gm) in anhydrous dimethylformamide (15 ml), potassium fluoride (1.22 gm) and 4-phenoxy-6-chloropyrimidine solution (0.98 gm of 4-phenoxy-6-chloropyrimidine in 10 ml of dimethylformamide) were added at 30-35?. The reaction mixture was then heated to 80? and stirred for 5-6 hours at 80°C. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass quenched with water (100 ml) and the product in the rection mass was extracted with ethyl acetate (100 ml). The extracted ethyl acetate layer was concentrated under vacuum to obtain a residue.
Yield: 1.7 gm; % Yield: 80%.

Example-7: Preparation of Compound of formula II

To a mixture of the compound of formula III (397 gm) in toluene (1985 ml), 2,4-thiazolidinedione (183.8 gm), acetic acid (18.85 gm) and piperidine (26.72 gm) were added. The reaction mixture was then stirred at reflux temperature for 5 hours in a Dean-Stark water trap apparatus. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to 30-35? for the precipitation. The resultant solid was filtered; washed twice with fresh anhydrous toluene (2 x 100 ml). The wet solid obtained was slurried in diisopropylether (500 ml) for 45 min and filtered. Yield: 302g; % Yield: 60%.

Example-8: Preparation of Lobeglitazone of formula I

To a mixture of compound of formula II (93 gm) and toluene (930 ml), Hantzsch ester (73.85 gm) and silica gel (279 gm) were added and then the reaction mixture was stirred at reflux temperature for 10-12 hours. The progress of the reaction mixture was monitored by HPLC. After completion of the reaction, the hot reaction mass was filtered, and the filter cake was washed with ethyl acetate (930 ml). The filtrates were combined and concentrated under vacuum to obtain a residue. The obtained residue was co-distilled twice with ethyl acetate (186 ml) at 55°C and mixed with hexane (500 ml). The contents were then stirred for 15 minutes at 50°C and decanted the hot hexane layer. The resulted sediment after decanting was concentrated under vacuum at 50°C to obtain a residue. The obtained residue was mixed with ethyl acetate (465 ml); heated to reflux; stirred for 1 hour; then cooled to 30-35? and stirred for 1 hour. The resultant solid was filtered under vacuum. The filtered wet solid was slurried in a mixture of methanol (100 ml) and acetone (100 ml) (1:1) at reflux temperature for 1 hour, then cooled to 30-35? and stirred for 1 hours at 30-35?. The resultant solid was filtered under vacuum; washed with a 1:1 mixture of methanol (25ml) and acetone (25 ml); and dried at 55? under vacuum.
Yield: 34 gm; % Yield: 36%.
Example-9: Preparation of Lobeglitazone of formula I

To a mixture of 1,4-dioxane (130 ml) and compound of formula II (3 gm) in a 400ml autoclave reactor, 10% Palladium on Carbon (3 gm) was added. 2 Kg/Cm2 H2 pressure was applied to the autoclave reactor and the reaction mixture was stirred for 5 hours at 30-35?. The progress of the reaction was monitored by HPLC. After completion of reaction, the reaction mass was unloaded, and the catalyst was removed by filtration. The filtrate was concentrated under vacuum to obtain a residue.
Yield without Purification: 2 gm; % Yield: 83%.

Example-10: Preparation of Lobeglitazone sulfate

To a mixture of Lobeglitazone (56 gm), dichloromethane (560 ml) and ethanol (73 ml), sulphuric acid (11.43 gm) was slowly added over 1 hour at 5-10°C and stirred for 1 hour at 2-10°C. The reaction mass was added to diisopropyl ether (1120 ml) at -5 to 5°C and then stirred for 1 hour at -5 to 5°C till the precipitation of solid. The resultant solid was filtered under vacuum and washed with diisopropyl ether (112 ml). The washed solid was slurried in heptane (560 ml) for 30 minutes and decanted the heptane layer. The resulted sediment after decanting was dissolved in a mixture of dichloromethane (560 ml) and ethanol (75 ml) and stirred for 30 minutes at 30-35? and concentrated under vacuum at 60? for 30 minutes to obtain a residue. The obtained residue was co-distilled with dichloromethane (560 ml), then slurried in heptane (500 ml) at 60? for 30 minutes. Decanted the heptane layer and then sediment was dissolved in a mixture of dichloromethane (560 ml) and ethanol (75 ml) and stirred for 30 minutes. The prepared solution was concentrated under vacuum at 60? to obtain a residue. The obtained residue was slurried with heptane (500 ml) at 60? for 30 minutes. Decanted the heptane layer and then sediment was filtered under vacuum under nitrogen and dried for 60 hours at 55?. Yield: 45 gm; % Yield: 66%; Total impurity content: 0.23% w/w.
,CLAIMS:
1. A process for preparing Lobeglitazone or its pharmaceutically acceptable salts thereof, comprising the steps of:
(i) reacting a compound of formula V,

with 4-hydroxybenzaldehyde in presence of a solvent to obtain a compound of formula IV,

wherein PG is an amino protecting group and R is a halogen group or a hydroxy group;

(ii) reacting the compound of formula IV with a compound of formula VIII in presence of a solvent,

to obtain a compound of formula III,

wherein X is a halogen group;

(iii) condensing the compound of formula III with thiazolidinone in presence of a solvent to obtain a compound of formula II;

(iv) reducing the compound of formula II in presence of a solvent to obtain Lobeglitazone of formula I; and

(v) optionally converting Lobeglitazone into its pharmaceutically acceptable salts thereof.

2. The process as claimed in claim 1, wherein the PG group of the compound of formula V in step (i) is selected from the amino protecting group comprising of carbobenzyloxy group, p-methoxybenzyl carbonyl group, tert-butyloxy-carbonyl group, 9-fluorenylmethyloxycarbonyl group, acetyl group, benzoyl group, benzyl group, carbamate group, p-methoxyphenyl group, and tosyl group.

3. The process as claimed in claim 1, wherein the R group of the compound of formula V in step (i) is selected from halogen group comprising of chloro, bromo, fluoro and iodo.

4.The process as claimed in claim 1, wherein the X group of the compound of formula VIII in step (ii) is selected from halogen group comprising of chloro, bromo, fluoro and iodo.

5. The process as claimed in claim 1, wherein the solvent in step (i) is selected from polar organic solvent comprising of alcohol selected from ethanol, methanol, or isopropanol; ketone selected from acetone or methyl isobutyl ketone; acetonitrile; dimethylformamide; dimethylsulfoxide; aromatic hydrocarbon selected from toluene or benzene; aliphatic hydrocarbon selected from hexane or heptane; and mixtures thereof.

6. The process as claimed in claim 1, wherein the solvent in step (ii) is selected from polar organic solvent comprising of alcohols selected from ethanol, methanol, or isopropanol; ketone selected from acetone or methyl isobutyl ketone; acetonitrile; dimethylformamide; dimethylsulfoxide; and mixtures thereof.

7. The process as claimed in claim 1, wherein the solvent in step (iii) is selected from organic solvent comprising of aliphatic hydrocarbons selected from hexane or heptane; aromatic hydrocarbons selected from toluene or benzene; chlorinated hydrocarbons selected from dichloromethane or chloroform; alcohol selected from ethanol or methanol; and mixtures thereof.

8. The process as claimed in claim 1, wherein the process of condensation in step (iii) employs piperidine, piperidinium acetate or benzoate.

9. The process as claimed in claim 1, wherein the process of reduction in step (iv) employs sodium borohydride or lithium borohydride or palladium.

10. The process as claimed in claim 1, wherein the solvent in step (iv) is selected from the group comprising of dimethylformamide; alcohol selected from ethanol or methanol; ethers selected from dioxane or tetrahydrofuran; ethyl acetate; aromatic hydrocarbon selected from benzene or toluene; and mixtures thereof.

11. The process as claimed in claim 1, wherein the process of reduction in step (iv) employs Hantzsch ester.

12. The process as claimed in claim 1, wherein the pharmaceutically acceptable salt of Lobeglitazone is Lobeglitazone sulfate.

13. A process for preparing a compound of formula III, comprising the steps of:
(i) reacting a compound of formula V

with 4-hydroxybenzaldehyde in presence of a solvent to obtain a compound of formula IV,

wherein PG is an amino protecting group and R is a halogen group or a hydroxy group; and

(ii) reacting the compound of formula IV with a compound of formula VIII in presence of a solvent,

to obtain a compound of formula III,

wherein X is a halogen group.

14. The process as claimed in claim 13, wherein the PG group of the compound of formula V in step (i) is selected from the amino protecting group comprising of carbobenzyloxy group, p-methoxybenzyl carbonyl group, tert-butyloxy-carbonyl group, 9-fluorenylmethyloxycarbonyl group, acetyl group, benzoyl group, benzyl group, carbamate group, p-methoxyphenyl group, and tosyl group.

15. The process as claimed in claim 13, wherein the R group of the compound of formula V in step (i) is selected from halogen group comprising of chloro, bromo, fluoro and iodo.

16. The process as claimed in claim 13, wherein the X group of the compound of formula VIII in step (ii) is selected from halogen group comprising of chloro, bromo, fluoro and iodo.

17. The process as claimed in claim 13, wherein the solvent in step (i) is selected from polar organic solvent comprising of alcohol selected from ethanol, methanol, or isopropanol; ketone selected from acetone or methyl isobutyl ketone; acetonitrile; dimethylformamide; dimethylsulfoxide; aromatic hydrocarbon selected from toluene or benzene; aliphatic hydrocarbon selected from hexane or heptane; and mixtures thereof.

18. The process as claimed in claim 13, wherein the solvent in step (ii) is selected from polar organic solvent comprising of alcohols selected from ethanol, methanol, or isopropanol; ketone selected from acetone or methyl isobutyl ketone; acetonitrile; dimethylformamide; dimethylsulfoxide; and mixtures thereof.