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A Process for the Preparation of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione and Salts Thereof.

IP.com Disclosure Number: IPCOM000179309D
Publication Date: 2009-Feb-12
Document File: 6 page(s) / 107K

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    A Process for the Preparation of 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione and Salts Thereof.

     5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione is a well-known anti-hyperglycaemic agent. Several processes have been reported for the preparation of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4- dione base and its salts.

    Provided is a process for the preparation of 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione comprising the reduction of 5-[4-[2- (N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene]-thiazolidine-2,4-dione:

    In one example, 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene]- thiazolidine-2,4-dione is combined with a cobalt ion, such as cobaltous chloride, cobaltous diacetate, and cobaltic chloride, a ligand, such as dimethylgyoxime, 2,2'- bipyridyl, and 1,10-phenanthroline, and a reducing agent, such as sodium borohydride, lithium borohydride, potassium borohydride, tetralkylammonium borohydride, zinc borohydride, and the like.

    The reaction may be carried out in the presence of a solvent selected from the group consisting of methanol, ethanol, isopropanol, acetone, dimethylformamide, tetrahydrofuran, water, and mixtures thereof.

    Typically, the reaction mixture is maintained at a temperature of about 20ºC to about 50ºC.

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    The obtained 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine- 2,4-dione was analyzed by X-ray Powder diffraction and found to contain crystal Form II as present in the following XRD pattern:

Main XRD peaks for the pattern are 13.56, 14.24, 16.72, 17.08, 17.48, 21.32,
22.12, 23.5 and 26.04 ± 0.2 degrees two theta.

    5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione can be further crystallized from a mixture of ethylacetate and methanol to obtain crystal Form I, as present in the following XRD pattern:

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Main XRD peaks for the pattern are 13.96, 16.67, 17.34, 20.25, 22.13 and 22.45 ±
0.2 degrees two theta.

Example-1: Preparation of 5-[4-[2-(N-methyl-N-(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, Base Form-I

Solution-A: 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene]-thiazolidine-2,4- dione (1.0 kg) was added to distilled water (3 L) followed by Tetrahydrofuran (5 L) at 25 to 30°C. 5.0% sodium hydroxide solution (2.5 L) was added slowly at 25 to 30°C to this solution. It was stirred for 30 minutes at 25 to 30°C and was cooled to 3°C to 15°C.

Solution-B: 180 gr of dimethylglyoxime were added to a 3.0 L solution of tetrahydrofuran and 20 gr Cobalt chloride at 25ºC to 30ºC.

Solution-B was added slowly to Solution-A at 3-15°C and the reaction mixture was stirred for 60 minutes at 3°C...