255 Nicotine Niflumic acid

Pyridine A Oxides. Analgesic and antiinflammatory dmgs niflumic acid [4394-00-7] (68) and pranoprofen [52549-17-4] (69) are manufactured from nicotinic acid N-oxide [2398-81 -4]. The antiulcer dmg omeprazole (66) is produced from 2,3,5-trimethylpyridine N-oxide [74409-42-0]. Zinc pyrithione, the zinc salt of pyrithione (45), is a fungicide derived from 2-chloropyridine N-oxide (45). 

Niflumic acid is prepared as follows Nicotinic acid, m-trifluoromethylaniline, and potassium iodide are intimately mixed and heated on an oil bath at 140°C. The mixture melts... 

Niflumic acid Niflumic acid, 2-3-(trifluoromethyl)anilino nicotinic acid (3.2.21), is synthesized either by the reaction of 2-chloronicotinic acid with 3-trifluoromethylaniline [84-86], or 2-aminonicotinic acid with l-bromo-3-trifluoromethylbenzene [87]. 

Niflumic acid is prepared as follows Nicotinic acid, m-trifluoromethylaniline, and potassium iodide are intimately mixed and heated on an oil bath at 140°C. The mixture melts to give a dark red liquid. The temperature of the oil bath is allowed to fall to 100°C and is maintained at this temperature for an hour and a half. The mixture puffs up and forms a yellow crystalline mass. After cooling to ordinary temperature, this mass is ground up in a mortar and extracted several times with small volumes of ether to remove excess m-trifluoromethylaniline. The residue is then washed twice with 10 ml of distilled water to remove m-trifluoromethylaniline hydrochloride and potassium iodide, and finally twice with 10 ml of 95% alcohol to remove colored resinous contaminants. After drying at 100°C, 2-(m-trifluoromethylanilino)nicotinic acid is obtained as pale yellow needles (from 70% ethanol) melting at 204°C (Kofler block). 

Good use is made of this chemistry in the synthesis of nifluminic acid 69, an analgesic with a pyridine ring. Disconnection of the C—N bond suggests a 2-chloropyridine 70 starting material easily derived from nicotinic acid 60 and a simple aromatic amine 72 available by functionalisation of trifluorobenzene 74. 69 Is actually available as niflumic acid from Aldrich. 

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