Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1997-12-12
1998-12-08
Killos, Paul J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
560156, 560180, 560 76, 558303, C07C 6938
Patent
active
058471987
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a process for the preparation of esters, in particular of fluorinated esters of dicarboxylic acids which comprise 2-fluoro- and 2,2-difluoro-malonic acid, and esters of 2-substituted-2-fluoro-malonic acids.
The use of elemental fluorine for the site specific fluorination of aliphatic compounds is rarely satisfactory due to the high reactivity of the element which leads to unspecific multiple substitution, carbon-carbon bond cleavage and oxidation. Because of the growing importance of fluorinated organic compounds in biochemical systems (R. Filler and Y. Kobayashi; Biochemical Aspects of Fluorine Chemistry; Elsevier Biomedical Press, New York, 1982.
J. T. Welch and S. Eswarakrishnan; Fluorine in Bioorganic Chemistry; John Wiley, New York, 1991) in recent years considerable effort has been devoted to finding ways of introducing fluorine into specific sites within molecules. Such molecules are valuable building blocks for the synthesis of biologically active compounds which have more complex structures. In this context, the preparation of fluoromalonic esters and difluoromalonic esters has aroused much interest since these compounds are useful intermediates in the preparation of bioactive molecules (T. Tsushima, K. Kawada, O. Shiratori and N. Uchida; Heterocycles, 1985, 1, 45). Hitherto, these compounds have been prepared by treating the alkali metal salts of malonic esters with an "electrophilic fluorinating agent" such as perchloryl fluoride (C. E. Inman, R. E. Oersterling and E. A. Tyczkowski; J Amer. Chem. Soc., 1958, 80, 6533), N-fluoro-N-sulphonamides (W E Barnette; J Amer. Chem. Soc., 1984, 106, 453), N-fluoro-2-pyridone (S. T. Purrington and W. A. Jones; J Org. Chem., 1983, 48, 761), N-fluoro-benzenesuphonimides (E. Differding and H. Ofner; Synlett., 1991, 187), N-Fluoro-pyridinium salts (with or without the addition of a Lewis acid) (T. Umemoto, S. Fukami, G. Tomizawa, K.K. Harasawa, K. Kawada and K. Tomita; J. Amer. Chem. Soc., 1990, 112, 8575), Chem., 1993, 58, 2791. R. E. Banks, N. J. Lawrence and A. L. popplewell; J. Chem. Soc., Chem. Commun., 1994, 343), N-fluoro-bis(perfluoroalkyl)sulphonimides (Z. Xu, D. D. Desmarteau and Y. Gotoh; J. Chem. Soc., Chem. Commun., 1991, 179. Z. Xu, D. D. Desmarteau and Y. Gotoh; J. Fluorine Chem., 1992, 58, 71. G. Resnati and D. D. Desmarteau; J. Org. Chem., 1991, 56, 4925), perfluoropiperidine (R. E. Banks and G. E. Williamson; Chem. Ind. (London), 1964, 1864) and acetyl hypofluorite (O. Lerman and S. Rozen; J. Org., Chem., 1983, 48, 724).
Although the treatment of alkali metal salts of malonic esters with electrophilic fluorinating agents can sometimes give high yields of the required mono- or di-fluorinated products, some of these reagents decompose fairly quickly, and the compounds from which they are made are often expensive or difficult to obtain.
Other methods for making esters of 2-fluoro- and 2,2,-difluoro-malonic acids are less direct. They are frequently inefficient, involve several steps in their synthesis or require starting materials which are expensive or difficult to obtain.
Thus, the prior art methods of preparing malonic esters are not satisfactory.
Surprisingly, we have now found a convenient and efficient process for the preparation of esters of 2-fluoro- and 2,2-difluoro-malonic acids which involves the use of elemental fluorine.
According to the present invention there is provided a process for the preparation of an ester having a formula 1: formula 2 as follows corresponding fluorinated compound of formula 1 by reaction with elemental fluorine.
In formulae 1 and 2, R.sub.1 and R.sub.3 are each independently selected from alkyl, cycloalkyl and aryl. For instance, each R.sub.1 and R.sub.3 group may be an n-alkyl group having from 1 to 4 carbon atoms.
In formulae 1 and 2, R.sub.2 is selected from hydrogen, alkyl, cyclo-alkyl, preferably C.sub.1-6 alkyl, nitro, cyano, halogen, alkoxy, acetamido, alkoxycarbonyl, aryloxycarbonyl and aryl.
Where R.sub.2 is formula 2 is hydrogen, R.sub.2 in formula 1 may be fluorine
Chambers Richard Dickinson
Hutchinson John
Thomson Julie
F2 Chemicals Limited
Keys Rosalynd
Killos Paul J.
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