The development of the glitazones (pioglitazone, rosiglitazone etc.) as drug substances has reduced the price of 2,4-thiazolidine-2,4-dione which is used in these syntheses.
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R=H |
KiloMentor has always been attracted to the idea that some neutral carbonyl impurities could be quickly separated away from a complex reaction mixture using chemical agents that would react with the crude and give rise to products that could be extracted into another liquid phase.
Several such methods have already been popularized. For example, that aldehydes and ketones could be separated from materials without these functional groups by treatment of a mixture with semicarbazide adsorbed on silica gel was taught by Suk Dev. These derivatives could be subsequently hydrolyzed and recovered from a cyclohexane solution (so long as they were soluble in this solvent). Another KiloMentor blog promoted formation of oximes which offered two possibilities for solid separation: as a crystalline derivative itself or a hydrochloride salt of the oxime. Oximes have been cleanly decomposed to recover the ketone using many different reagents.
Thiazolidine-2,4-dione, it would seem, is a reagent that could be used to separate a carbonyl component, present as an impurity in a reaction mixture, where a non-carbonyl substance predominates and is the constituent of interest. This works because the condensation product between thiazolidinedione and a carbonyl along with any excess thiazolidinedione reactant will dissolve in a strong base because the thiazolidinedione has an acidic salt-forming imide functionality. It must be noted though, that the carbonyl compound itself cannot be regenerated. This is different from what was possible in the cases already alluded to.
Thiazolidine-2,4-dione has melting point of 123-126 C. It can be purchased for less than $100/kg. The reaction can be done in a melt of this compound with sodium acetate as catalyst. Thiazolidine-2,4-dione is known to react easily with both aldehydes and ketones to give condensation products at its reactive methylene. With ketones, a mixture of two geometric isomers may be formed but both products upon treatment with aqueous alkali can be deprotonated to salts that have the potential to be extracted into an aqueous solution. Thus, these products show promise to be separable from neutral non-carbonyl materials by liquid-liquid extraction. Although only aryl aldehydes and aryl ketones seem to have been used in the literature, there is no good reason why aliphatic ketones would not also react cleanly particularly in the presence of an excess of the thiazolidinedione reagent. Aliphatic aldehydes might be too sensitive and could polymerize.
US 4703052
In a typical such reaction, the aldehyde or ketone starting material (IV) and thiazolidinedione (VI) are combined in approximately equimolar amounts with a molar excess, preferably a 2-4 fold molar excess, of anhydrous sodium acetate, and the mixture is heated at a temperature high enough to affect melting, at which temperature the reaction is substantially complete in from about 5 to 60 minutes. The desired olefin of formula (III) is then isolated, for example, by mixing with water and filtration, to obtain the crude product, which is purified, if desired, e.g. by crystallization or by standard chromatographic methods.
A mixture of carbonyls or a single carbonyl impurity in a non-carbonyl product might be separated by treating the mixture with thiazolidine-2,4-dione and sodium acetate and acetic anhydride with or without a solvent in order to condense the more reactive compound with the thiazolidine-2,4-dione. This condensed product will have an acidic hydrogen on the imide which can be converted to a sodium or potassium salt that can allow extraction into an aqueous solution. The residual, more hindered carbonyl or the non-carbonyl containing compound will remain unreacted and can be recovered by treatment with an organic solvent in which it readily dissolves. Any excess thiazolidine-2,4-dione present will also dissolve in the aqueous alkaline solution.
This methodology would need to be demonstrated with a mixture of ketones with different degrees of steric hindrance. A similar methodology has been used by partially forming enamines with the more reactive of two carbonyls and distilling the unreactive compound away from the enamine substance. The method proposed here does not require that the compounds be sufficiently low molecular weight to be volatile.
CA2423978
The invention also provides a process for preparing the potassium salt or a solvate thereof, characterized in that 5-[4-[2-(N-methylW(2- pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (Compound (I)) or a salt thereof, preferably dispersed or dissolved in a suitable solvent, is reacted with a source of potassium ion and thereafter, if required, a solvate of the resulting potassium salt is recovered. A suitable reaction solvent is an alkanol, for example, propan-2-ol, or a hydrocarbon, such as toluene, a ketone, such as acetone, an ester, such as ethyl acetate, an ether such as tetrahydrofuran, a nitrile such as acetonitrile, or a halogenated hydrocarbon such as dichloromethane, or water; or a mixture thereof. Conveniently, the source of potassium ion is potassium hydroxide. The potassium hydroxide is preferably added as a solid or in solution, for example in water or a lower alcohol such as methanol, ethanol, or propan-2-ol, or a mixture of solvents. An alternative source of potassium ion is a potassium alkoxide salt for example potassium tertiary butoxide.
EXAMPLES
Example 1
5-[4-[2-(N-Methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4- dione, potassium salt
A solution of potassium hydroxide (0.56 g) in water (5 ml) was added to a stirred solution of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethyl]thiazolidine-2,4-dione (3.0 g) in tetrahydrofuran (30 ml) at 50°C. The solution was cooled with stirring to 21°C over approximately 1 hour, before the solvent was evaporated under reduced pressure to afford 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, potassium salt (2.90 g) as a crystalline solid.
Example 2
5-[4-[2-(N-Methyl-N-(2-pyridy1)amino)ethoxyl benzyl] thiazolidine-2,4- dione, potassium salt
A stirred suspension of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl] thiazolidine-2,4-dione (3.0 g) in acetone (30 ml) was heated to reflux before a solution of potassium hydroxide (0.56 g) in water (5 ml) was added. After 5 minutes a clear solution was formed and the temperature of the stirred solution was lowered to 21°C over approximately 1 hour. The solvent was evaporated under reduced pressure to give the 5- [4-[2-(N-methyl-N-(2-pyridyl)mino)ethoxy]benzyl]thiazolidine-2,4-dione, potassium salt (3.25 g) as a crystalline solid.
Example 3
5-[4-[2-(N-Methyl-N-(2-pyridyl)amino)ethoxy]benzyI]thiazolidine-2,4- dione, potassium salt
A solution of potassium hydroxide (0.56 g) in water (1 ml) was added to a stirred suspension of 5-[4-[2-(N-methy1-N-(2-pyridy1)amino)ethoxy]benzy1]thiaz01idine-2,4- dione (3.0 g) in propan-2-ol (30 ml) at reflux. Within 5 minutes the solution became clear before a precipitate began to form. The stirred mixture was cooled to 21°C over approximately 90 minutes. The solid precipitate was collected by filtration, washed with propan-2-01 (1 0 ml) and dried under vacuum for 16 hours to afford 5-[4-[2-(N-methyl-N- (2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione, potassium salt (3.14 g) as a white crystalline solid.
Found (%): C: 54.44, H: 4.53, N: 10.45; Expect: C: 54.52, H: 4.83, N: 10.60.
The potassium ion level was determined as 9.9% by wt (expect: 9.9%) by ion
chromatography. Water content (Karl-Fisher): 0.2 % by wt.
Example 4
5-[4-[2-(N-Methyl-N-(2-pyridy1)amino)ethoxyl benzyl] thiazolidine-2,4- dione, potassium salt
Potassium t-butoxide (1.41 g) was added to a stirred suspension of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4-dione (3.0 g) in ethyl acetate (30 ml) at reflux. The stirred mixture was maintained at reflux for 15 minutes and then cooled to 21ºC over approximately 1 hour. The solid was collected by filtration, washed with ethyl acetate (10 ml) and dried under vacuum at 50°C for 72 hours to yield the 5-[4-[2-(Nniet1iy1- N-(2-pyridy1)amino)ethoxy]benzy1]thiazo1idine-2,4-dione7 potassium salt (3 30 g) as a white crystalline solid.
Example 5
5-[4-[2-(N-MethyI-N-(2-pyridyl)amino)ethoxy]benzyl]thiazolidine-2,4- dione, potassium salt
A solution of potassium hydroxide (4.71 g) in water (5.0 ml) was added to a stirred suspension of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzy1]thiazolidin-2,4- dione (25.0 g) in propan-2-ol1 (250 ml) at reflux. The stirred mixture was maintained at reflux for 15 minutes and then cooled to 21ºC over approximately 1 hour. The solid was collected by filtration, washed with propan-2-01 (50 ml) and dried under vacuum at 60°C for 16 hours to afford the 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl] thiazolidine-2,4-dione, potassium salt (26.6 g) as a white crystalline solid.
Pertinent reference
J. Org. Chem., 1956, 21 (11), pp 1269–1271
A possible common use
Friedel-Craft acylations usually proceed with o,p-orientation to an electron-donating aromatic substituent. It seems possible that the para-substituted product could preferentially react with an insufficient quantity of 2,4-thiazolidinedione at its less sterically hindered carbonyl or if the reaction is reversible the para-substituted compound could produce the more thermodynamically stable product compared to the ortho-substituted compound and thus produce mixtures of predominantly unreacted ortho compound and thiazolidinedione adducts of the para compound. Upon dilution with water, the thiazolidinedione product may crystallize leaving unreacted ortho ketone or upon aqueous alkali/organic solvent partition the thiazolidinedione adduct would go to the aqueous phase and the ortho-substituted product to the organic layer.
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