Synthesis Of Thiazolidinediones And Its Derivatives

2,4-thiazolidinedione is an important intermediate that is used to synthesize manifold pharmaceuticals. A series of thiazolidine-2,4-diones was obtained by the chemical modifications of the substituents at the 3-position or the 5-position of the thiazolidine ring, among of which had different pharmacological properties. A number of them have been underwent clinical or preclinical investigation to treat a certain diseases. In recent years, as a newly insulin sensitzers, several thiazolidinedine derivatives having 5-substitute-2, 4-thiazolidinedione structures were developed and there has been a resurgence of interest in the development of novel antihyperglycemic agents which can reverse the insulin resistance in non-insulin-dependent diabetes mellitus patients. Thiazolidinediones exert their effects by stimulating the Peroxisome proliferator activated receptor- y (PPAR- y ) which is predominantly expressed in adipose tissue and leading to the reduced production of many factors that were believed to cause insulin resistance. In addition to their hypoglycemic effect, thiazolidinediones can also alleviate many abnomalities associated with " insulin resistance syndrome" (IRS). Now, diabetesmellitus that is severe non-contagion ailment is followed by tumour and macrovascular and cardiovascular diseases. The development of thiazolidinediones as a newly insulin sensitzers will have singnificant positive impacts on the treatment of type 2 diabetes and other conditions associate with insulin resistance.Objective: To develop a modification of the general route for the synthesis of 2,4-thiazolidinedione (I) and its derivatives which are 5-(4-hydroxybenzyl)thiazolidine-2,4-dione (II), 5-[4-[2-N-Methyl-N-(2-pyridyl)amino]ethoxyl-]benzylthiazolidine-2,4-dione (Rosiglitazone, III ) and 5-[4-[2-( 1 -indolyl)ethoxy]benzyl]thiazolidine-2,4-dione(I V).Methods: compound (I) was synthesized by using thiourea and ethyl chloroacetate as raw materials. The reaction of thiaourea with ethyl chloroactate through cyclocondenstion, neutralization with sodium acetate afforded 2-imino-4-thiazolidone that is pseudothiohydanto-in then subjected to acid hydrolysis to obtain 2,4-thiazolidinedione.Compound (II) was synthesized by using three different compounds as raw materials through three different synthetic routes respectively. The first route was as follows: diazotization of p-aminophenol and subsequent Meerwin arylation reaction with ethyl acrylate gave ethyl 2-chloro-3-(4-hydroxyphenyl) propionate followed the cyclocondensation with thiourea, then subjected to acidhydrolysis to obtain 5-(4-hydroxybenzyl)thiazolidine-2,4-dione. The second route was as follows: diazotization of p-nitroaniline and subsequent Meerwin arylation reaction with ethyl aery late gave ethyl 2-chloro-3-(4-nitrophenyl) propionate followed the cyclocondensation with thiourea yielded 5-(4-nitrobenzyl)thiazolidine-2,4-dione, which was reduced in the presence of iron powder/ammonium chloride to give 5-(4-aminobenzyl)thiazolidine-2,4-dione, then subjected to diazotization and acid hydrolysis to obtain 5-(4-hydroxy-benzyl)thiazolidine-2,4-dione.The third route was as follows: the p-hydroxybenzaldehyde underwent Knoevenagal condensation with compound (I) in the presence of piperdinium benzoate in refluxing toluene with azeotropic removal of water to give 5-(4-hydroxybenzylid-ene)thiazolidine-2,4-dione, which was reducede by magnesium /methanol to obtain 5-(4-hydroxybenzyl)thiazo-lidine-2,4-dione.Compound (III) was synthesized by using 2-chloro-pyridine as raw materials. The reaction of 2-chloro-pyridine with 2-(methylamino)ethanol under nitrogen afforded 2-(methyl-2-pyridinylamino)ethanol, then subjected to condesation with /-fluorobenzaldehyde in the presence of TEBA which as a phase transfer catalyst to obtain 4-[2-N-methyl-N-(2-pyridyl)amino]ethoxyl]benzal-dehyde, which followed the Knoevenagal condensation with 2,4-thiazoli-dinedione (I) gave 5-[4-[2-N-methyl-N-(-2-pyridyl)amino)ethoxyl]phenyl]-methylene]thiazolidine-2, 4-dione, which were redu...