This invention relates generally to plural-substituted pyridine derivatives and, particularly, to processes for preparing and isolating 5-trifluoromethyl-2-pyridone and for using same.
Although a large number of functionally substituted pyridine compounds are known and capable of synthesis, certain patterns of disubstitution on the pyridine ring are difficult to obtain by any convenient and commercially viable means. Pyridines having functional substituents in the 2- and 5- positions of the ring are often valuable derivatives, but fall within this category. For example, hydroxyl, cyano, carboxy, chloro and other groups are difficult to introduce into these positions on the pyridine ring.
It has long been known that certain non-nitrogen-containing heterocycles can assist in this regard because of their ability to be converted into pyridine bases. Pyrones, pyrilium salts and furans are examples of such transformations. As early as 1884 in Ber., 17, 2384 (1884), Von Pechmann et al. described the conversion of 5-carboxy-2-pyrone to 5-carboxy-2-hydroxypyridine upon treatment with ammonia in the presence of a caustic material such as sodium hydroxide. ##STR2## Although this reaction is potentially useful in some commercial applications, the number of reported uses of the method is small.
This 5-carboxy-2-hydroxypyridine, also known as 6-hydroxynicotinic acid and 5-carboxy-2-pyridone, is an example of a disubstituted pyridine of some commercial value. Besides this Von Pechmann et al. method, it has been prepared directly from a pyridine in two known instances. First, synthesis has been achieved by direct carboxylation of 2-hydroxypyridine, as depicted below. ##STR3## As can be seen, this procedure is rather lengthy and has proven not a viable commercial method. Second, 2-hydroxy-5-carboxypyridine has been prepared directly from 5-carboxypyridine, also known as niacin, through known techniques.
Trifluoromethyl-substituted pyridines have also proven to be valuable derivatives of pyridine bases, although difficult to obtain. Synthesis of these compounds has been accomplished in only a limited number of cases, most of which have involved the conversion of a pyridine carboxylic acid to a trifluoromethyl pyridine utilizing sulfur tetrafluoride.
Accordingly, it is generally known that alkyl and aromatic carboxylic acids react with sulfur tetrafluoride in the presence of hydrogen fluoride to give trifluoromethyl derivatives. ##STR4## This reaction has been applied to amino acids. Kobayashi et al.: Chem. Pharm. Bull. 15, 1896 (1967), M. S. Raasch: J. Org. Chem., 27, 1406 (1962). It has also been applied in a few reports to simple pyridine carboxylic acids such as niacin and 3,5-dicarboxypyridine. Kobayashi et al. and Raasch, id.
It is likewise generally known that some esters and anhydrides of these carboxylic acids react with sulfur tetrafluoride to give the corresponding fluorinated ethers. In the case of compounds such as ethyl acetate and dichloromaleic anhydride, the double-bonded oxygen groups are simply replaced during the fluorination reaction. W. R. Hasek, W. C. Smith, and V. A. Engelhardt, J. Amer. Chem. Soc., 82, 543 (1960). ##STR5##
The presence of a hydroxy group leads to undesirable reactions involving this additional oxygen function in the trifluoromethylation reaction. As used herein, "trifluoromethylation" refers to the conversion of a precursor material to a material containing a trifluoromethyl radical by the addition or substitution of fluorine to the precursor material. As background for this statement, 2- and 4-hydroxypyridines have been shown to physically exist as a mixture of tautomeric forms, appearing both as the hydroxy and the amide derivatives. R. Elderfield, Heterocyclic Compounds, 1, 435-440 (1950). ##STR6## For this reason, these hydroxypyridines undergo reactions typical of both phenols and amides as also reported in the Elderfield reference. ##STR7## Similar behavior has been reported in substituted hydroxypyridines such as the 5-carboxy-2-hydroxypyridines discussed above. Klingsberg, Pyridine and Its Derivatives, Part Three, p. 646 (1962).
It is known that hydroxy groups give rise to fluoro groups by standard substitution upon treatment with sulfur tetrafluoride. Boswell et al., Org. Reactions, 21 p. 12 (1973). It is also known that amides react with sulfur tetrafluoride to give a variety of products. Hasel, Smith and Engelhart, J. Amer. Chem. Soc., 82, 543, (1966) For example, if the amide contains at least one nitrogen-hydrogen bond, cleavage at the nitrogen-carbon bond is reported to occur. ##STR8## This cleavage is believed to be caused by trace amounts of hydrogen fluoride produced during the reaction. Hasek, Smith & Englehart, J. Amer. Chem. Soc., 82, 543 (1966).
Therefore, disubstituted 2- and 5-pyridine derivatives are often difficult to obtain. This statement is particularly true, as taught by the art, with the 2-hydroxy and 5-trifluoromethyl substituents. Nevertheless, 5-trifluoromethyl-2-pyridone is now proving to be a desirable and valuable commercial compound based on both proven and anticipated uses as shown in the art. It appears from the prior art that 5-trifluoromethyl-2-pyridone would be useful as a catalyst in nucleophilic aromatic substitution, formation of amides, and hydrolysis of esters. It also appears from the prior art that 5-trifluoromethyl-2-pyridone would be useful as an antioxidant. Still further, this compound is proving to be a valuable intermediate in the synthesis of herbicides, pharmaceuticals, germicides and the like. See U.S. Pat. No. 4,038,396 to Shen et al. This is due at least in part to the ready substitution for the 2-hydroxy group on the ring and the lower toxicity caused by the 5-trifluoromethyl substituent.
The only reported synthesis of 5-trifluoromethyl-2-pyridone in the art attempts to avoid the prior art problems discussed above. This synthesis, reported in U.S. Pat. No. 4,038,396 issued to Shen et al. on July 26, 1977, teaches a three-step method in Example 111 (beginning at column 23, line 62) for preparing 5-trifluoromethyl-2-pyridone (the tautomeric form of 5-trifluoromethyl-2-hydroxypyridine) from 6-hydroxynicotinic acid. This method includes steps for specifically circumventing the expected interference of the tautomeric hydroxy and amide forms of the initial compound. This is accomplished by converting the 2-substituent to a chloro group in an attempt to protect the 2- position during the trifluoromethylation reaction.
In particular, Shen et al. first teach converting this 6-hydroxynicotinic acid to a less-reactive 6-chloronicotinic acid by a reaction involving liquid phosphorous oxychloride added jointly with solid phosphorous pentachloride and then recaptured in water. The 6-chloro derivative is then subjected to trifluoromethylation using sulfur tetrafluoride in the presence of hydrogen fluoride, and the 2-chloro-5-trifluoromethylpyridine is reconverted back to the hydroxy or amide derivative through a complex treatment under nitrogen with silver acetate in the presence of acetic acid.
This three-step Shen et al. procedure is lengthy and complex, and thus of minimal commercial valuable. It further emphasizes the need for the development of a viable, more efficient process for preparing the valuable 5-trifluoromethyl-2-pyridone. ##STR9##