Field of invention:
The present invention relates to process for preparing Pioglitazone and it's pharmaceutically acceptable salts of Formula-VII known for the treatment of non-insulin dependent diabetes.
Background of the invention:
Non-insulin-dependent diabetes mellitus (NIDDM) is a metabolic disorder leading to long-term complications and premature atherosclerosis. Compounds of class like, sulfonylureas, biguanides were used for treatment of patients suffering from such disorders. Substituted arylthiazoiidinediones demonstrated potent activity towards non-insulin dependent diabetes. A number of thiazolidinedione derivatives which are disclosed as having hypoglycemic and hypolipidaemic activity.
Pioglitazone selectively stimulates nuclear gamma-receptors, activated by peroxisome proliferator (PPAR). It modulates the transcription of the insulin sensitive genes involved in the control of glucose and lipid metabolism in the lipidic, muscular tissues and in the liver. Pioglitazone does not directly stimulate insulin secretion, but rather affects the insulin-synthetic function of the pancreas. Pioglitazone also reduces insulin resistance in the liver and peripheral tissues, increases the expense of insulin-dependent glucose, decreases withdrawal of glucose from the liver; reduces quantity of glucose, insulin and glycated haemoglobin in the bloodstream. Pioglitazone decreases the level of triglycerides and increases that of high-density lipoproteins without changing low-density lipoproteins and general cholesterol in patients with disorders of the lipid metabolism.
US Patent 4,812,570, discloses the process for the preparation of thiazolidinediones wherein, the time taken for the preparation of 4-[2-(5-ethyl-2-pyridyl)ethoxy]benzaldehyde is 10- 20 hours and the yields are low. This compound reacts with 2,4-thiazolidinedione in presence of piperidine in ethanol to give 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzylidene}-2,4-th iazolidinedione which on further reduction yields pioglitazone.
US Patent 5,554,758 and US Patent 6,100,403 disclose the process wherein the benzaldehyde ether derivatives are formed via Williamson coupling of 4-hydrOxy

benzaldehyde with a mesylate or tosylate of alcohol in presence of base. 4-[2-(5-ethyl-2-pyridyl)ethoxy] benzaldehyde formed, which is reacted with 2,4-thiazolidinedione to afford benzyl idene-2,4-thiazol id inone. It is further subjected to reduction of the double bond of this compound result in the formation of crude compound of pioglitazone.
For the reduction of double bond several transition metal catalysed hydrogenation conditions are reported. They are low yielding and the reaction may not go for completion with starting material remaining as an impurity. To obtain reasonably pure samples in most of the reported conditions the reduction has been performed with 100-300 % w/w excess of Pd/C under very high pressures ranging between 50-100 kg cm"2 and the temperature varying between room temperature to 100°C.
US Patent 5,585,495 discloses the cobalt-catalysed reduction of the double bond of 5-{4-[2-(5-ethyl-2-pyridyl)ethoxy]benzylidene}-2,4-thiazolidinedione. The method described is faster, easier and results in improved yields and convenient for scale up. The method claims to eliminate the operational and safety problems associated with handling of pyrophoric Pd/C and high pressure hydrogenation.
Thus there is need for the alternate, more convenient, improved process for producing Pioglitazone and its pharmaceuticals acceptable salts on industrial scale.
Summary of the invention:
Main aspect of the present invention is relates to provide an improved process for the production of Pioglitazone and its pharmaceutically acceptable salts.
Another aspect of the present invention is relates to provide hydrogenation reaction is carried out with less quantity of catalyst and under less hydrogen pressure.
Yet another aspect of the present invention is relates to provide improved quality of intermediate and final product.

Detailed description of the invention:
The present invention describes an improved process for the production of Pioglitazone and its pharmaceutically acceptable salts which comprises the steps of:
(a) reacting Formula (I) with Formula (II) to obtain Formula (III);
(b) coupling Formula (III) with/^-hydroxy benzaldehyde to get Formula (IV);
(c) condensing of Formula (IV) with 2,4-thiazolidinedione in presence of base and suitable solvent to get Formula (V) and converting it to salt;
(d) reducing Formula (V) salt in the presence of catalyst under hydrogen pressure and solvent to get Formula (VI); and
(e) converting Formula (VI) into its pharmaceutically acceptable addition salts,
Accordingly the process in the present invention is described in scheme I
According to the scheme I, Formula-I is reacted with R]S02X (Formula-II) where Ri is an alkyl or an aryl group and X is an halo group comprising the compounds methyl sulfonylchloride, ethyl sulfonylbromide, propyl sulfonylchloride, phenylsulfonyl chloride,^-tolylsulfonyl chloride preferably alkyl sulfonylhalide to form compound of Formula-Ill in a solvent at the reaction temperature in the range of about -20°C to 60°C preferably -10°C to 40°C in presence of a base. Halogens are selected from fluorine, chlorine, bromine and iodine and alkyl groups are selected from C|-C4-alkyls and aryl groups are selected from phenyl, tolyl etc.


Compound of Formula-IH is reacted with />-hydroxybenzaldehyde in presence of a base in a suitable solvent in presence of a phase transfer catalyst to form compound of Formuia-IV. The reaction is carried out at a temperature range of about 60°C to 100°C with the slow addition of compound of Formula-Ill for about 1-8 hrs preferably 2-5 hrs. The advantage of the process is minimization of vinyl pyridine impurity. The product yields obtained by this process are high compared to the prior art processes.
Suitable Solvent described above is selected from chlorinated solvents such as dichloromethane, dichloroethane, carbon tetrachloride, chloroform or hydrocarrxwi solvents such as benzene, toluene, xylene and others such as dimethylformamide. Bases are selected from inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, or organic bases selected form triethylamine, morpholine, N-methyl piperidine etc., Phase transfer catalysts is selected from benzyl tributylammonium bromide, benzyl triethylammonium chloride, tetrabutylammonium bromide, cetyl trimethylammonium chloride and like. Compound of Formula-IV obtained is condensed with 2,4-thiazolidinedione in a suitable solvent and a base. Suitable solvent is selected from alcohol such as methanol, ethanol, propanol; dimethyl formamide, dimethyl sulfoxide, acetonitrile, dioxane, acetic acid etc., and the base is selected from amine such as ammonia, optionally substituted by Q-C4 alkyl, pyrrolidine, piperidine, morpholine, piperazine, triethylamine, alkali metal/alkaline earth metal alkoxides, carbonates, bicarbonates,

hydroxides like sodium methoxide, potassium carbonate, sodium bicarbonate, calcium hydroxide etc.. Condensation reaction is generally conducted at 45°C to reflux temperature and generally for about 1-45 hrs preferably 8 to 25 hrs. Condensed benzylidene derivative is converted to inorganic acid addition salt by the addition of mineral acid preferably sulphuric acid or phosphoric acid in C!-C4 alkanolic solvents, acetic acid and like to obtain the compound of Formula-V.
Compound of Formula-V is catalyticaliy reduced to obtain Formula-VI in presence of suitable solvent. Suitable solvent is selected from alcohols such as methanol, ethanol, propanol, ethers such as dimethoxy ethane, dioxane, tetrahydrofuran etc., dimethyl formamide, ethylacetate, acetic acid etc., or mixtures thereof. Catalyst employed can be selected from palladium black, palladium on carbon, raney nickel or palladium on barium carbonate preferably palladium carbon. The reaction is carried out under a pressure of not more than 30 kg/cm2 for 20-60 hours. Finally the salt is neutralized with a base to form thizolidinedione. Base for neutralization is selected from amines such as ammonia, optionally substituted by C1-C4 alky], alkali metal/alkaline earth metal alkoxides, carbonates, bicarbonates, hydroxides like sodium methoxide, potassium carbonate, sodium bicarbonate, calcium hydroxide etc. The advantage of the process is substantial conversion of starting material and formation of less impurity and also not involving high pressures. Purification steps are reduced which is industrially time consuming and laborious.
Formula-VI thus obtained is converted to pharmaceutical^ acceptable salts by reacting with inorganic acids to form thiazolidinedione inorganic acid addition salts. Preferred mineral acid is hydrochloric acid. Hydrochloric acid is added as an alkanolic solution such as in methanol, ethanol, isopropanol, preferably as solution in methanol.

The following non-limiting examples illustrate specific embodiments of the present invention. They are, not intended to be limiting the scope of present invention in any way.
Examples
Example-1: Preparation of 4-[2-(5-ethyl-2-pyridyl)ethoxyjbenzaldehyde.
To a mixture of (5-ethyl-2-pyridyl)ethanol (lOg) and toluene (8ml) was added triethyl amine (8.5g). The mixture was cooled to -5 to -10°C and slowly added Mesyl chloride solution (lOg in 20 ml toluene) and maintained the temperature of the reaction mass. DM water (50ml) was added to the reaction mass. Separated the organic layer and washed with DM water (50ml). Again separated the organic layer and extracted the aqueous layer with toluene (20ml). Sodium hydroxide solution (4.5g in 34 ml DM water), p-hydroxybenzaldehyde (12g) and tributyl benzylammonium chloride (3.5g) were slowly added to the organic layer at heating. The reaction mass was cooled and added water (120ml), separated the organic layer and extracted with IN sodium hydroxide (3 X 60ml). Filtered the reaction mass through hyflo bed and washed with toluene (10ml). Filtrate is dried with sodium sulfate (5g), distilled off toluene under vacuum. Yield: 12.5-15.0 g.
Example-2: Preparation of 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzilidene-2,4-thiazolidinedione Sulfate.
To a mixture of 4-[2-(5-ethyl-2-pyridyl)ethoxy]benzaldehyde (15g) and methanol (120ml) was added 2,4-thiazoIidinedione (6g), piperidine (3g). The mixture was heated to reflux and added piperidine (0.5g). Cooled the reaction mass and adjusted the pH to 6.0-7.0 by 50% acetic acid solution. Filtered the solid and washed the cake with methanol (10ml). Added methanol (9ml) to the wet material and heated to reflux. Cooled the reaction mass, filtered and washed the cake with methanol (10ml). Added methanol (170ml) to the wet material and cooled the reaction mass. Adjusted the pH of the reaction mass to 1.0-2.0 with 25% sulfuric acid. Filtered the reaction mass and washed the cake witii methanol (10ml). Dry the solid. Yield: 12-16g.

Example-3: Preparation of 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl-2,4-thiazolidinedione.
5-[4-[2-(5-ethyl-2-pyridyi)ethoxy]benzilidene-2,4-thiazolidinedione Sulfate (10g), acetic acid (60ml) and DM water (35ml) was heated to 50-70DC. Added 10% Pd/C (5g) and applied hydrogen gas pressure (9-12kg/cm2) and maintained. Added 10% Pd/C with acetic acid. Cooled the reaction mass, filtered and washed with acetic acid (10 ml). Distilled off the filtrate and methanol (100ml) was added. Adjusted pH of the reaction mass to 6.5-7.0 with aqueous ammonia solution, filtered and washed with methanol (10ml). Added DM water (50ml) to the wet material, filter and wash the cake with DM water (20ml). Dry the material under vacuum till LOD is <2.0%w/w to get 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl-2,4-thiazolidinedione. Yield: 5.5-6.5g.
ExampIe-4: Preparation of 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl-2,4-tbiazolidinedione Hydrochloride.
5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzy 1-2,4-thiazolidinedione (lOg) and methanolic HCI (60ml) was heated to 40-60°C. Filtered the reaction mass and washed the cake with methanolic HCI (10ml). Heated the reaction mass to 40-60DC and slowly cooled. Added seeding material (50mg) and maintained the reaction mass for 1-2 hrs. Filtered the reaction mass and washed with chilled ethanol (10ml). Added ethanol (100ml) to the wet material and heated the reaction mass to reflux. Cooled the reaction mass to room temperature, filtered and washed the cake with ethanol (10ml). Dry the material under vacuum till LOD is <5.0%w/w to get 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl-2,4-thiazolidinedione HCI. Yield: 5.5-7.5g.

We Claim:
1. A process for the production of Pioglitazone and its pharmaceutically
acceptable salts which comprises the steps of:
(a) reacting Formula (I) with Formula (II) to obtain Formula (III);
(b) coupling Formula (III) with p-hydroxy benzaldehyde to get Formula (IV);
(c) condensing of Formula (IV) with 2,4-thiazolidinedione in presence of base and suitable solvent to get Formula (V) and converting it to salt;
(d) reducing Formula (V) salt in the presence of catalyst under hydrogen pressure and solvent to get Formula (VI); and
(e) converting Formula (VI) into its pharmaceutical ly acceptable addition salts.

2. The process according to claim 1, wherein Formula II is methyl sulfonylchloride, ethyl sulfonylbromide, propyl sulfonylchloride, phenylsulfonyl chloride and p-tolylsulfonyl chloride.
3. The process according to claim 1, wherein base used is amine such as ammonia, optionally substituted C]-C4 alkyl, pyrrolidine, piperidine, morpholine, piperazine, triethylamine, alkali/alkaline earth metal alkoxide, carbonate, bicarbonate, hydroxide such as sodium methoxide, potassium carbonate, sodium bicarbonate, calcium hydroxide.
4. The process according to claim lc, wherein suitable solvent used is alcohol such as methanol, ethanol, propanol; dimethyl formamide; dimethyl sulfoxide; acetonitrile; dioxane and acetic acid.
5. The process according to claim 1, wherein catalyst used is palladium black, palladium on carbon, raney nickel or palladium on barium carbonate.
6. The process according to claim Id, wherein solvent used is alcohol such as methanol, ethanol, propanol; ether such as dimethoxy ethane, dioxane, tetrahydrofuran; dimethyl formamide; ethylacetate and acetic acid or mixture
thereof.

7. The process according to claim 1, wherein hydrogen pressure is not more than
30 kg/cm2.
8. A process for the production of Pioglitazone and its pharmaceuticaily
acceptable salts which comprises the steps of:
a) reducing Formula (V) sulfate salt in the presence of catalyst under
hydrogen pressure to get Formula (VI); and
b) converting Formula (VI) into its pharmaceuticaily acceptable addition
salts.
9. The process according to claim 8, wherein catalyst used is palladium black, palladium on carbon, raney nickel or palladium on barium carbonate.
10. The process according to claim 8 wherein solvent used for reduction reaction is alcohol such as methanol, ethanol, propanol; ether such as dimethoxy ethane, dioxane, tetrahydrofuran; dimethyl formamide; ethylacetate and acetic acid or mixture thereof.