Direct fluorination process for preparing high purity...

Details Direct fluorination process for preparing high purity... Direct fluorination process for preparing high purity...

1999-11-01

2002-09-24

Rotman, Alan L. (Department: 1623)

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

Organic compounds

Carboxylic acid esters

C560S178000, C568S393000

Reexamination Certificate

active

06455728

ABSTRACT:

CROSS-REFERENCE TO RELATED APPLICATIONS
Not applicable.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not applicable.
BACKGROUND OF THE INVENTION
This invention relates to processes for fluorinating &bgr;-dicarbonyls to form the corresponding &agr;-fluorinated-&bgr;-dicarbonyl compounds.
Previously, &bgr;-dicarbonyls, such as &bgr;-diketones and &bgr;-ketoesters, having the formula:
where R
1
is H, alkyl or alkoxy, R
2
is H, alkyl or perfluoroalkyl, and R
3
is H, Cl, Br, I or alkyl, have been fluorinated directly with fluorine in acidic solvents or in polar solvents containing acidic, or weakly basic, polar additives. See, e.g., U.S. Pat. No. 5,569,778 (Umemoto et al.) and WO 95/14646 (Chambers et al.). This technology has proven reasonably selective for those diketones and ketoesters which are stabilized in the enol form under the chosen solvent conditions. Even with substrate loadings of only 5-10 wt. %, however, the desired monofluorinated products still contain 10-15% radical fluorination impurities (the term “radical fluorination impurities” refers to products resulting from fluorination at R
1
and/or R
2
in Formula I above).
EP 0891962 (Nukui et al.) discloses a process for preparing fluorinated dicarbonyl compounds comprising reacting dicarbonyl compounds and fluorine gas without any solvent and in the presence of at least one acid selected from the group consisting of trifluoromethanesulfonic acid (i.e., triflic acid), methanesulfonic acid, hydrofluoric acid, sulfuric acid, trifluoroacetic acid, boron trifluoride and sulfonated polymers. Nukui et al. discloses in Example 1 that methyl-3-oxopentanoate can be fluorinated in the absence of solvent with triflic acid as an additive, to give only 16% fluorination impurities, including 2,2-difluorinated impurity. The yield was reported to be high only when 2.5 equivalents of fluorine were added.
Ketoesters containing perfluoroalkyl groups are only effectively fluorinated in nonpolar solvents. Under these conditions, 30% radical fluorination is observed. For all of the dicarbonyl substrates, fluorinated impurities are often difficult to separate and many of them are carried forward in subsequent chemical steps.
A further problem in direct fluorinations with formic acid, trifluoroacetic acid and/or triflic acid, has been that fluorine use has been inefficient. Between 1.6 and 4 times the stoichiometric amount of fluorine has been required to obtain high conversions with these acid additives.
Accordingly, it is desired to directly fluorinate &bgr;-dicarbonyl compounds by a process that does not suffer from the foregoing deficiencies in the art.
All references cited herein are incorporated herein by reference in their entireties.
BRIEF SUMMARY OF THE INVENTION
The invention comprises a process for providing an &agr;-fluorinated-&bgr;-dicarbonyl compound, said process comprising directly fluorinating a &bgr;-dicarbonyl compound with fluorine to provide the &agr;-fluorinated-&bgr;-dicarbonyl compound, wherein the direct fluorination is conducted in a reactive medium. The reactive medium preferably comprises a radical scavenger, such as oxygen, that inhibits side reactions between fluorine and acid additives.
BRIEF DESCRIPTION OF SEVERAL VIEWS OF THE DRAWINGS
Not applicable.
DETAILED DESCRIPTION OF THE INVENTION
Embodiments of the invention comprise a process which uses dilute oxygen as a radical scavenger for the direct fluorination of &bgr;-dicarbonyl compounds, as shown in
where R
1
is H, alkyl or alkoxy, R
2
is H, alkyl or perfluoroalkyl, and R
3
is H, Cl, Br, I or alkyl. The products of the inventive process (e.g., 2-fluoro-1,3-dicarbonyls) are important precursors to fluorinated heterocycles used in the pharmaceutical industry.
Conventional processes of direct fluorination typically provide fluorinated carbonyl products which are only 75-85% pure and contaminated with radical fluorination byproducts, which are difficult to separate. Use of oxygen in the fluorine stream can lightly lower the overall isolated yield, but after washing with water, yields a product which is 90-96% pure and containing radical fluorination impurity levels which are 5-20% lower than when oxygen is not used. Use of oxygen in the fluorine stream inhibits side reactions between fluorine and acid additives used in direct fluorination (e.g., formic acid, trifluoroacetic acid, and/or triflic acid) so that less fluorine is required to give high substrate conversion.
In embodiments of the inventive process, F
2
/N
2
mixtures are diluted with air to give dilute F
2
/O
2
/N
2
mixtures, which are sparged into solutions of the substrate in an acidic solvent (for ketoesters where R
2
=R
f
, the solvent is CFCl
3
). The gas mixture can suitably comprise about 1 to about 50% F
2
, about 0.1% to about 50% O
2
and about 0 to about 99% N
2
, preferably about 5 to about 25% F
2
, about 1 to about 25% O
2
and about 50 to about 95% N
2
, more preferably about 10 to about 20% F
2
, about 10 to about 20% O
2
and about 60 to about 80% N
2
. At high conversions, less than 5% radical fluorination byproducts are observed.
Surprisingly, when oxygen is added during the fluorination, ketoesters (where R
2
=R
f
) can be fluorinated selectively without a solvent. When fluorinated neat in the absence of oxygen, these compounds char, giving only a small amount of the desired product. The process, therefore, offers the advantage of significantly higher product purity obtained at much higher reaction loadings.


REFERENCES:
patent: 2614129 (1952-10-01), McBee et al.
patent: 4036864 (1977-07-01), Barton et al.
patent: 4284558 (1981-08-01), Barton et al.
patent: 5569778 (1996-10-01), Umemoto et al.
patent: 0891962 (1999-01-01), None
patent: WO 95/14646 (1995-06-01), None
patent: WO 97/35824 (1997-10-01), None
Chambers et al, Direct Fluorination of 1,3- Dicarbonyl Compounds, Tetrahedron, 52(1), p. 1-8, Jan. 1996.*
Chambers et al, Direct of Fluorination of 1,3- Dicarbonyl compounds, J. Chem. Soc., Chem. Commun., (1), 21-2, Jan. 1995.*
Appelman, “Isolation and Characterization of Acetyl Hypofluorite” J. Am. Chem. Soc. 1985, 1076515-6518.

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