P-Chlorophenoxyisobutyric acid

The ethyl p-chlorophenoxyisobutyrate may be obtained by heating a mixture of 206 parts of dry p-chlorophenoxyisobutyric acid, 1,000 parts of ethanol and 40 parts of concentrated sulfuric acid under reflux during 5 hours. The aicohol is then distilled off and the residue is diluted with water and extracted with chioroform. The chloroform extract is washed with sodium hydrogen carbonate solution, dried over sodium sulfate and the chloroform removed by distillation. The residue is distilled under reduced pressure and there is obtained ethyl p-chlorophenoxyisobutyrate, BP 148° to 150°C/20 mm. 

The p-chlorophenoxyisobutyric acid used as starting material may be obtained as follows. 

When addition is complete the mixture is heated under reflux during 5 hours and then the acetone is removed by distillation. The residue is dissolved in water, acidified with hydrochloric acid and the mixture extracted with chloroform. The chloroform extract is stirred with sodium hydrogen carbonate solution and the aqueous layer is separated. The alkaline extract is acidified with hydrochloric acid and filtered. The solid product is drained free from oil on a filter pump, then washed with petroleum ether (BP 40° to 60°C), and dried at 50°C. The solid residue, MP 114° to 116°C, may be crystallized from methanol (with the addition of charcoal) to give p-chlorophenoxyisobutyric acid, MP 118° to 119°C. 

The p-chlorophenoxyisobutyric acid used as starting material may be obtained as follows. A mixture of 200 parts of p-chlorophenol, 1,000 parts of acetone and 360 parts of sodium hydroxide pellets is heated under reflux and 240 parts of chloroform are gradually added at such a rate that the mixture continues to reflux without further application of heat. 

Clofibrate is rapidly and completely absorbed after oral administration. It is hydrolyzed to clofibric acid during absorption and in its passage through the liver. The acid binds strongly to plasma proteins. Sixty percent of it is excreted as glucuronide conjugate in the urine. Some is secreted into the bile and reabsorbed. The plasma elimination half-life is 25 h. Clofibrate appears in plasma as p-chlorophenoxyisobutyric acid. An acyl-linked metabolite of clofibrate has been identified in human urine. 

Gas-Liquid Chromatographic Determination of p-Chlorophenoxyisobutyric Acid and Its Comparison to an Ultraviolet Method... 

Chemical Name 2-(4-Chlorophenoxy)-2-methylpropanoic acid ethyl ester Common Name Ethyl p-chlorophenoxyisobutyrate Structural Formula ... 

Clofibrate, the prototype of the fibric-acid derivatives, is the ethyl ester of p-chlorophenoxyisobutyrate. Gemfibrozil is a nonhalogenated phenoxypentanoic acid and thus is distinct from the halo-generated number of fibric-acid analogs (e.g., fenofibrate, bezafibrate, and ciprofibrate have been developed and are used). 

This syndrome of myalgia, stiffness, weakness and malaise, commonly with an increase in serum enzymes, is well-recognized (SED VIII, p. 934), and in the past evidence has been advanced that it may be more common in patients with the nephrotic syndrome. In 1975, Pierides et al. pointed to the possible complications if the drug is used in chronic renal faUure. When treating 5 uraemic patients with 1 -2 g clofibrate daily, they recorded muscle weakness and tenderness as weU as a rise in serum creatine kinase. Excessive accumulation of both total and free serum chlorophenoxyisobutyric acid (C.P.I.B.), the active metabolite of clofibrate, was found in the 3 patients in whom it was sought (4 ). Their view that clofibrate should in renal failure be used very cautiously or not at all is supported by the report from Spain on a similar case where administration of 1.5 g clofibrate daily for 9 days to a patient undergoing dialysis resulted in a muscular syndrome with elevation of SCOT, SGTP, CPK, LDH and aldolase (5 ). 

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