A METHOD FOR PREPARATION OF THIAZOLIDINEDIONE

DERIVATIVES

FIELD OF THE INVENTION

The present invention discloses a new method of preparing organic compounds. In particular, the present invention provides a new solvent system for reduction method to prepare few specific pharmaceutically active compounds in particular thiazolidinedione derivatives, including Pioglitazone, Rosiglitazone, Ciglitazone and Eπglitazone. These compounds are known for the treatment of diabetes.

BACKGROUND AND PRIOR ART OF THE INVENTION Thiazolidine derivatives are useful for the treatment of diabetes. The effect on insulin resistance of thiazolidine derivatives are described, e.g. in, Chang, et al, Diabetes 32: 839-845 ( 1983) and Chang, et al, Diabetes 32:830-838 (1983). The preparation of these thiazolidinedione derivatives includes the reduction of an intermediate previously performed by a troublesome high pressure hydrogenation using palladium on carbon or raπney nickel as catalyst. To avoid difficulties in hydrogenation, the need is an easy and efficient method of reduction.

1391 82 (1988); Chem- Abstr., 109:6504h (1988); disclose the process for making thiazolidinedione derivatives, using hydrogen on a palladium on carbon catalyst.

D.A- Clark et al-. J- Med. Chem., 34:319-325 (1991 ) discloses the process for making substituted dihydrobenzopyran and dihydrobenzofuran thiazolidine-2,4-diones, using hydrogen on a palladium on carbon catalyst.

The preparation of these thiazolidinedione derivatives like Pioglitazone, Englitazone, Ciglitazone and Rosiglitazone includes the reduction of an intermediate previously performed by a troublesome high pressure hydrogenation on a palladium on carbon catalyst. Presently it is needed an easier, more efficient method for this reduction.

US 5,585.495 discuss the use of cobalt ion with a ligaπd and reducing agent for the new reduction method for making certain pharmaceutically active compounds, such as thiazolidinedione derivatives.

The following references disclose cobalt catalyzed reductions: U. Leutenegger et a!.. Angew. C hem. InL Ed., 28:60 ( 1989) discloses the enantioselective reduction of α, β- unsaturated carboxylates with sodium borohydride and catalytic amounts of chiral cobalt semicorrin complexes; and M.N. Ricroch and A. Gaudemer, J- Organometal. Chem.. 67: 1 19 ( 1974) discloses (pyridinato) cobaloxiine, chloro (pyridinato) cobaloxime and vitamin B12 catalyzing the hydrogenalion of α, β-unsaturated esters by hydrogen or sodium borohydride. J. O. Oshy, et aL J.A.C.S. 108:67-72 (1986), discloses cobalt (Et)-mediated sodium borohydride and lithium aluminum hydride reductions, which do not involve the use of ligands.

WO 93/13095, WO 04/007490 and WO 06/026934 disclose method of reduction for the antihyperglycemic Pioglitazone, Englitazone, Ciglitazone and Rosiglitazone. However, they do not disclose method of instant invention including the solvent used and its recovery enabling, it to be used for subsequent reduction reactions.

The present invention provides new and effective process for reducing thiazolidinedione derivatives. The present invention particularly provides the use of a solvent during the reduction of thiazolidinedione derivatives which is easy to handle and having effective reaction timings. Interestingly, the recovery of the solvent after the reaction will reduce cost of the production. This method also helps in better effluent management.

The present method is economical and can be advantageously applied on an industrial scale. The method yields thiazolidinedione derivatives in a quality needed for pharmaceutical substances.

OBJECTS OF THE INVENTION

The main object of the present invention is to obtain a method for preparation of thiazolidinedione derivatives by reducing intermediates of thiazolidinedione derivatives having double bonds.

Another object of the present invention is to obtain a method for preparation of thiazolidinedione derivatives at a temperature ranging between 0-25 ⁰ C.

Yet another object of the present invention is to obtain a method for preparation of thiazolidinedione derivatives which is industrially viable and cost effective.

Still another object of the present invention is to obtain a method for preparation of thiazolidinedione derivatives which provides for recovery of the solvent that can be used for future reactions.

Still another object of the present invention is to obtain a method for preparation of thiazolidinedione derivatives by employing cheaper and easily available raw-materials.

Still another object of the present invention is to obtain a method for preparation of thiazolidinedione derivatives which reduces the cost of production and helps in better effluent management.

STATEMENT OF THE INVENTION

Accordingly, the present invention relates to a method for preparation of thiazolidinedione derivatives by reducing intermediates of thiazolidinedione derivatives having double bonds at temperature ranging between 0 to 25°C comprises, (a) adding sodium hydroxide solution into suspension of the intermediates of thiazolidinedione derivatives having double bonds in a mixture of polyethylene glycol and water; (b) adding metal ligand complex catalysts of bivalent metals in presence of at least one complexing agent; (c) adding sodium borohydride in alkaline solution and stirring; (d) adding acetone to quench the reaction; (e) adjusting pH with acid; (f) isolating crystals by addition of water; and (g) optionally re-using mother liquor as a solvent for future reduction reactions by basifying to pH values more than 9.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a method for preparation of thiazolidinedione derivatives by reducing intermediates of thiazolidinedione derivatives having double bonds at temperature ranging between 0 to 25 ⁰ C comprises,

a. adding sodium hydroxide solution into suspension of the intermediates of thiazolidinedione derivatives having double bonds in a mixture of polyethylene glycol and water; b. adding metal ligand complex catalysts of bivalent metals in presence of at least one complexing agent; c. adding sodium borohydride in alkaline solution and stirring; d. adding acetone to quench the reaction; e. adjusting pH with acid; f. isolating crystals by addition of water; and g. optionally re-using mother liquor as a solvent for future reduction reactions by basifying to pH values more than 9.

In yet another embodiment of the present invention, the bivalent metal is cobalt.

In still another embodiment of the present invention, the alkaline solution is aqueous solution of sodium hydroxide.

In still another embodiment of the present invention, the polyethylene glycol is polyethylene glycol-400 grade.

In still another embodiment of the present invention, the pH is adjusted in the range between 4 to 6.5. In still another embodiment of the present invention, the acid is selected from a group comprising citric acid, tartaric acid, acetic acid or mixtures thereof.

In still another embodiment of the present invention, the thiazolidinedione derivatives are selected from a group comprising pioglitazone, englitazone, ciglitazone and rosiglitazone. The present invention provides a process for reducing thiazolidinedione derivatives like Pioglitazone, Englitazone, Ciglitazone and Rosiglitazone using cobalt ion, a ligand and a reducing agent. This process employs temperature in the range of 0-15 ⁰ C and a suitable solvent which is mixture of solvents, viz. polyethylene glycol and water.

PIOG LlTAZONE

ROSIGL1TAZONE

This process wherein the cobalt ion is in the form of cobaltous chloride hexahydrate, the ligand is dimethyl glyoxime in N, N dimethyl formamide and the reducing agent is sodium borohydride.

The method selected gives substantially pure product by using easily available solvent with a significant yield improvement.

The present method is economical and can be advantageously applied on an industrial scale. The method yields thiazolidinedione derivatives in a quality needed for pharmaceutical substances

The present invention offers a reduction reaction in polyethylene glycol, which is more efficient because it is faster, easier and results in substantially improved yield of the desired product. It is also more convenient for scale up at plant, since no high-pressure hydrogenators are required. This also involves the recovery of the solvent which in turn reduces the cost of the production and better effluent management.

The present invention offers the reduction of thiazolidine derivatives which involves the reagents cobalt ion in the form of cobaltous chloride hexahydrate, the ligand dimethyl glyoxime in N, N dimethyl formamide, the reducing agent sodium borohydride and the solvent media for the reaction is polyethylene glycol.

Polyethylene glycol present in the mother liquor is used for future reactions without distillation or any other treatment for purification.

Reduction of thiazolidinedione derivative involves reacting thiazolidinedione derivative having double bond in a mixture of Polyethylene glycol-400 and water in the alkaline condition with metal ligand complex and a reducing agent at a controlled temperature ranging from 0 to 15°C. Metal ion of metal ligand complex is selected from bivalent metals, preferably cobalt in the form of cobaltous chloride. The said ligand is an aromatic or aliphatic ligand, preferably dimethyl glyoxime. Reducing agents used are selected from Lithium borohydride, Potassium borohydride and Sodium borohydride. Suitable temperature conditions for the reduction are 0- 15 ⁰ C. Preferable temperature condition for the said reduction reaction for the addition of reagents is 0-5° C. Preferred temperature condition for the reduction reaction is 10 to 15°C.The reaction mixture is stirred for about 1 8 hrs and quenched by the addition of acetone at lower temperature, further reaction mass is neutralized by the addition of acetic acid. The crystals are isolated by the addition of water and stirred at 10- 15 ⁰ C followed by filtration and drying.

For further reactions, the mother liquor of the reaction mass can be taken as the solvent media by adjusting pH of the solution to 9-9.5 by aqueous solution of sodium hydroxide. The recovery of the solvent polyethylene glycol reduces the cost of production and helps in better effluent management.

The invention is further elaborated with the help of following examples. However, these examples should not be construed to limit the scope of invention.

Example 1

Sodium hydroxide (9.26g) in water (160ml) is added to the suspension of N-(2-{4-[(E)- (2,4-dimethylidene-l,3-thiazolidin-5-ylidene)methyl]phenyl}e thyl)-N-methylpyridin-2-

amine (10Og) in polyethylene glycol - 400 (500ml) and water (800ml) at 10-15 ⁰ C followed by the addition of cobaltous chloride hexahydrate (0.08g), Dimethyl glyoxime (1.39g) in N, N dimethyl formamide (30ml) at the same temperature. The reaction mass is further cooled to 0-5 ⁰ C and a solution of sodium borohydride (22.8g) and sodium hydroxide (0.46g) in water (140ml) is added at 0-5 ⁰ C and stirred for 18 hrs.

Acetone (160ml) is added to the reaction mass after the completion of the reaction at 0- 5°C and stirred well and the pH of the reaction mass is adjusted to 6-6.5 using glacial acetic acid. Water (lit) is added to the reaction mass and stirred at 10-15 ⁰ C for 2hrs. The crystals formed are filtered followed by water wash and drying under high vacuum. Yield: 90%

Example 2

DMG PIOGLITAZONE

Sodium hydroxide (9.26g) in water (160ml) is added to the suspension of ((5£)-5-({4- [2-(5-ethylpyridin-2-yl)ethoxy)phenyl}methylidene)-l,3-thiaz olidine-2,4-dione (10Og) in polyethylene glycol - 400 (500ml) and water (800ml) at 10-15 ⁰ C followed by the addition of cobaltous chloride hexahydrate (0.08g), Dimethyl glyoxime (1.39g) in N, N dimethyl formamide (30ml) at the same temperature. The reaction mass is further cooled to 0-5 ⁰ C and a solution of sodium borohydride (22.8g) and sodium hydroxide (0.46g) in water (140ml) is added at 0-5 ⁰ C and stirred for 18 hrs.

Acetone (160ml) is added to the reaction mass after the completion of the reaction at 0- 5 ⁰ C and stirred well and the pH of the reaction mass is adjusted to 6-6.5 using glacial

acetic acid. Water (l it) is added to the reaction mass and stirred at 10-15 ⁰ C for 2hrs. The crystals formed are filtered followed by water wash and drying under high vacuum.

Yield: 88%

Example 3

Reuse of PEG- 400:

Suspension of N-(2-{4-[(£)-(2,4-dimethylidene-l,3-thiazolidin-5- ylidene)methyl]phenyl}ethyl)-N-methylpyridin-2-amine (10Og,) in the filtrate (after the crystallization of Rosiglitazone from example 1) containing PEG 400 ,water and acetic acid is basified to pH 9.0 to 9.5 using solution of sodium hydroxide in water at 10- 15°C. Cobaltous chloride hexahydrate (0.08g), Dimethyl glyoxime (1.39g) in ν, ν dimethyl formamide (30ml) are added at the same temperature. The reaction mass is further cooled to 0-5 ⁰ C and a solution of sodium borohydride (22.8g) and sodium hydroxide (0.46g) in water (140ml) is added at 0-5 ⁰ C and stirred for 18 hrs. Acetone (160ml) is added to the reaction mass after the completion of the reaction at 0- 5°C and stirred well and the pH of the reaction mass is adjusted to 6-6.5 using glacial acetic acid. Water (lit) is added to the reaction mass and stirred at 10-15 ⁰ C for 2hrs. The crystals formed are Filtered followed by water wash and drying under high vacuum.

Yield: 87%