High purity preparation of fluorinated 1,3-dicarbonyls using...

Details High purity preparation of fluorinated 1,3-dicarbonyls using... High purity preparation of fluorinated 1,3-dicarbonyls using...

2000-07-19

2001-10-23

Richter, Johann (Department: 1621)

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

Organic compounds

Oxygen containing

C570S201000, C570S203000

Reexamination Certificate

active

06307105

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 electrophilically fluorinating &bgr;-dicarbonyls to form the corresponding &agr;-fluorinated-&bgr;-dicarbonyls, with the use of bis-fluoroxydifluoromethane (BDM) in the presence of an acid.
Although bis-fluoroxydifluoromethane (CF
2
(OF)
2
), and to a much greater extent the monofluoroxy compound, fluoroxytrifluoromethane (CF
3
OF), have been used to carry out a number of electrophilic fluorinations (see, e.g., U.S. Pat. No. 4,766243 and Fifolt et al., “Fluorination of Aromatic Derivatives with Fluoroxytrifluoromethane and Bis(fluoroxy)difluoromethane,” J. Org. Chem. 1985, 50(23), 4576), the inventors are not aware of any prior art teaching their use for the fluorination of 1,3-dicarbonyls.
On the other hand, there is evidence in the art suggesting that O—F bond-containing compounds are not particularly effective for fluorinating 1,3-dicarbonyls. For example, the use of acetyl hypofluorite, another O—F bond containing compound, has been used successfully in the fluorination of enolate salts of ketoesters, but has proven to be less effective in the fluorination of neutral ketoesters. See, e.g., Patrick, “Electrophillic Fluorination of Carbon-Hydrogen Bonds,” Chemistry of Organic Fluorine Compounds II 1995, 133. Similarly, cesium fluoroxysulfate (CsSO
3
(OF)) gave only a 44% yield of the desired monofluorinated product and 19% of the difluorinated product on reaction with relatively nucleophilic 2,4-pentanedione. See, e.g., Stavber et al., “Room-temperature Reactions of CsSO
4
F with Organic Molecules containing Heteroatoms,” J. Chem. Soc., Chem. Comm., 1983, 563.
Previously, 1,3-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. While this methodology has been reasonably selective, the desired monofluorination products still contain 10-35% 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) at substrate loadings of only 5-10 wt. % in the chosen solvent. See, e.g., U.S. Pat. No. 5,569,778 (Umemoto et al.)
Another technique for fluorinating the alpha carbon in &bgr;-dicarbonyls comprises directly fluorinating &bgr;-dicarbonyl compounds with fluorine in a reactive medium comprising a radical scavenger, such as oxygen, that inhibits side reactions between fluorine and acid additives. See the inventors' prior U.S. patent application Ser. No. 09/432,723, filed Nov. 1, 1999.
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 that the substrate loadings have been substantially increased in very strong acids (up to 88 wt. % methyl-3-oxopentanoate (MOP) in highly acidic triflic acid), but gives only 16 wt. % fluorination impurities, including 2,2-difluorinated impurity. However, these fluorinated impurities are often difficult to separate from the desired product and many of them are carried forward in subsequent reaction steps.
Additionally, higher purity fluorinated dicarbonyls have been obtained by a number of multistep methods. For example, the dicarbonyl compound has been converted, using a strong base, into its enolate salt which has been fluorinated by a more selective, but costly, electrophilic fluorinating reagent. By this method, the dicarbonyl compound has been chlorinated and then fluorinated by halogen exchange. This method gives only moderate yields (30-80%) of fluorinated product, which must still be purified by fractional distillation. See, e.g., U.S. Pat. No. 5,391,811 (Böhm et al).
Despite the foregoing developments, there is still room in the art for improved fluorination methods.
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, said process comprising electrophilically fluorinating a &bgr;-dicarbonyl with bis-fluoroxydifluoromethane in the presence of an acid to provide said &agr;-fluorinated-&bgr;-dicarbonyl.
BRIEF DESCRIPTION OF SEVERAL VIEWS OF THE DRAWINGS
Not applicable.
DETAILED DESCRIPTION OF THE INVENTION
A preferred process of the invention comprises electrophilically substituting a single fluorine group on the alpha-carbon of a &bgr;-dicarbonyl by reacting the &bgr;-dicarbonyl with bis-fluoroxydifluoromethane (BDM) in the presence of an acid, as shown in Equation I:
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., &agr;-monofluorinated-&bgr;-dicarbonyls, such as methyl-2-fluoro-3-oxopentanoate) 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. On the other hand, the instant invention, comprising the use of bis-fluoroxydifluoromethane, provides selectivity (for the &agr;-monofluorinated-&bgr;-dicarbonyl product) in an amount from about 88 to about 96% in the fluorination of the neat &bgr;-dicarbonyl compound to which small amounts of acid have been added. The selectivity is even greater for embodiments of the invention comprising fluorinating a 10-25 wt. % solution of the substrate in an acid. Such embodiments provide selectivity from about 95% to 100% preferably, about 99% to 100%, more preferably about 99.5 to 100%. Thus, preferred embodiments of the invention limit the amount of radical fluorination impurities to less than 12%, more preferably 4% or less, and even more preferably less than 0.5%.
&bgr;-dicarbonyl substrates suitable for use in the invention include, e.g., methyl-3-oxopentanoate, ethyl-4,4,4-trifluoroacetoacetate, 2,4-pentanedione and other diketones and ketoesters of the form shown in Formula I and Equation I, above. Accordingly, typical products of the invention include, e.g., methyl-2-fluoro-3-oxopentanoate, ethyl-2,4,4,4-tetrafluoroacetoacetate, 3-fluoro-2,4-pentanedione and other &agr;-fluoro-&bgr;-dicarbonyls of the form shown in Equation I, above.
Hydrofluoric acid (HF) is the preferred acid catalyst of the invention, but other suitable acid catalysts include, e.g., triflic, fluorosulfonic, sulfuric, formic, acetic and trifluoroacetic acids, and Lewis acids such as BF
3
.
In embodiments of the inventive process, BDM is produced in a flow system from F
2
and CO
2
. In these and other embodiments of the invention, BDM and any additional components, such as F
2
, are preferably charged into a reactor (e.g., an FEP reactor) in an inert carrier, such as nitrogen, CO
2
, dry air, Ar, He, etc. The ratio (volume:volume) of BDM to inert carrier is preferably about 0.5:99.5 to about 10:90, preferably 3:97 to 5:95. Ratios outside these ranges are either impractical or hard to control because of reaction exothermicity.
It is preferred to add about 1 to 1.5, preferably 1 to 1.2 equivalents of electrophile (e.g., BDM or BDM/F
2
) to the substrate. Adding more than 1.5 equivalents is inefficient and/or promotes undesirable side reactions. Adding less than 1 equivalent leaves a portion of the substrate unreacted.
In embodiments where BDM and F
2
are used as electrophiles, the ratio (

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