Fluorination of ketoamides

Details Fluorination of ketoamides Fluorination of ketoamides

1999-12-09

2002-05-14

Kumar, Shailendra (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C564S200000, C564S209000

Reexamination Certificate

active

06388133

ABSTRACT:

This application is a 371 of PCT/GB97/02002, filed Jul. 24, 1997.
This invention relates to the fluorination of ketoamides and in particular to the fluorination of N,N-disubstituted-&bgr;-ketoamides.
There is much interest in the preparation of fluorinated-1,3-dicarbonyl compounds since they are useful building blocks for the preparation of more complex molecules containing fluorine that are of potential value to both the pharmaceutical and agrochemical industries. For example, the replacement of the 2-hydrogen by fluorine in N,N-disubstituted-1,3-ketoamides affords fluorinated products that may be used in the preparation of potentially useful bio-active molecules. Hitherto, this transformation has been carried out by treating N,N-disubstituted-1,3-ketoamides with electrophilic fluorinating reagents such as 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo-[2.2.2]octane.bi(tetrafluoroborate) sold under the Trade Mark SELECTFLUOR (R E Banks, N J Lawrence and A L Popplewell; J Chem Soc., Chem Commun., 1994, 343). However, such reagents are expensive, often unstable, difficult to handle and require fluorine for their preparation. There would seem to be advantage in carrying out the transformation directly using elemental fluorine, but unfortunately its use for the site specific fluorination of aliphatic compounds is rarely satisfactory due to its high reactivity which leads to unspecific multiple substitution, carbon-carbon bond cleavage and oxidation.
WO95/14646 discloses a method for the fluorination of certain 1,3-diketones and 1,3-ketoesters using elemental fluorine.
Surprisingly, we have now found that elemental fluorine can be used to convert N,N-disubstituted-1,3-ketoamides into the corresponding 2-fluoro-compounds in good yield. According to the present invention, there is provided a process for the preparation of an N,N-disubstituted-2-fluoro-1,3-ketoamide having the formula RCO.CFR′CONR
2
″ which comprises treating an N,N-disubstituted-1,3-ketoamide having the formula RCO.CHR′CONR
2
″ with elemental fluorine, wherein the groups R, R′ and R″ are independently selected from alkyl, aryl, substituted aryl, cycloalkyl, and substituted cycloalkyl and wherein the group R′ may also be nitro or chlorine.
Preferably, the group R contains from 1 to 12 carbon atoms and the groups R′ and R″ contain from 1 to 8 carbon atoms. More preferably, the groups R, R′ and R″ contain from 1 to 6 carbon atoms.
Preferably, the fluorine is diluted with an inert gas such as nitrogen, helium or argon. The concentration of fluorine is preferably in the range 1-50 vol. %, more preferably from 2-25 vol. % and most preferably from 5-15 vol. %.
Preferably, the N,N-disubstituted-1,3-ketoamide is present in a solvent which is substantially inert to fluorine. Examples of such solvents are neutral substances such as acetonitryl and water, or acid substances such as formic acid. The solvent may be a mixture of these types of solvent.
Preferably, the concentration of N,N-disubstituted-1,3-ketoamide in the solvent is from 0.1 mol/l to 10 mol/l, although higher concentrations may be used.
Preferably, the reaction is carried out at a temperature in the range −60° C. to +150° C., more preferably from −20° C. to +50° C. and most preferably from −10° C. to +15° C.


REFERENCES:
patent: 5049698 (1991-09-01), Newland
patent: 5362919 (1994-11-01), Costeloo et al.
patent: 5525729 (1996-06-01), Cabrera et al.
patent: 5756000 (1998-05-01), Hansen et al.
patent: 0667332 (1995-08-01), None
patent: WO 95/14646 (1995-06-01), None
Banks et al.; Efficient Electrophilic Fluorination of&bgr;-Dicarbonyl Compounds with the Selectfluor Reagent F-TEDA-BF4(1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane, J. Chem. Soc., Chem. Commun., 343-344 (1994).
International Search Report, PCT/GB97/02002.
March;Advanced Organic Chemistry, 4thEdition, pp. 534, 587 (1992).

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