Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-01-27
2001-02-06
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S486000
Reexamination Certificate
active
06184394
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention pertains to the preparation of 3-furoate esters and to certain novel intermediate compounds. More particularly, this invention pertains to a two-step process wherein a 4-acyl-2,3-dihydrofuran is converted to a 2-alkoxy-3-acyl-3-halotetrahydrofuran which then is contacted with an alkoxide to produce an alkyl 3-furoate. The 2-alkoxy-3-acyl-3-halotetrahydrofuran intermediates are novel compounds.
Unlike 2-furoic acid and its esters which are derived from inexpensive furfural, 3-furoic acid and its esters have been, in the past, difficult and expensive to synthesize in any amount. Preparation of 3-substituted furans from furan itself requires multiple steps because the 2-position of furan is more activated toward aromatic substitution reactions. Although several literature references describe methods to produce 3-substituted furans, many contain comments on the difficulty of synthesizing such compounds. For example, S. P. Tanis states in
Tetrahedron Letters,
23, 3115-3118 (1982): “Although many methods have been reported for the synthesis of 3-substituted furans they generally require many steps, relatively inaccessible starting materials, or proceed in low overall yields.”
Most literature processes for the preparation of 3-furoic acid or ester involve the decarboxylation of furandicarboxylic acids. T. Reichstein, et al.,
Helv. Chim. Acta,
15, 268-273 (1932); 16, 276-281 (1933), reported the preparation of 3-furoic acid from either furan-2,3-dicarboxylic acid, furan-3,4-dicarboxylic acid or furan-2,4-dicarboxylic acid. These dicarboxylic acids are obtained in low yield via several intermediate steps. See also D. Dare, et al.,
J. Chem. Soc., Perkin I,
1130-1134 (1973); M. Boyd, et al.,
Synthesis,
545-546 (1971); L. W. Deady, et al.,
Synthesis,
571 (1972). In a simplification of Reichstein's process, E. Sherman, et al. decarboxylated furantetracarboxylic acid to give 3-furoic acid (
J. Am. Chem. Soc.,
72, 2195-2199 (1950)). Gilman, et al.,
J. Am. Chem. Soc.,
55, 2903-2909 (1933) reported the decarboxylation of 2,4-furandicarboxylic acid to 3-furoic acid which was converted to ethyl 3-furoate via 3-furoyl chloride.
3-Bromofuran can be converted into 3-furoic acid by reaction with butyl lithium to give 3-lithiofuran followed by reaction with carbon dioxide (Y. Fukuyama, et al.,
Synthesis,
443-444 (1974); I. Fleming, et al.,
Synthesis,
898 (1985)) or by electrocarboxylation (O. Sock, et al.,
Tetrahedron Letters,
26, 1509-1512 (1985)). These methods, however, are expensive and difficult to adapt to commercial scale operation. Additionally, 3-bromofuran is prohibitively expensive for use as a starting material.
Other processes for preparing 3-furoic acid and esters thereof include (1) the rhodium-catalyzed reaction of alkyl formyldiazoacetate with vinyl ethers (E. Wenkert, et al.,
J. Organic Chem.,
55, 4975-4976 (1990)); (2) Diels Alder reactions of oxazoles with propiolic acid or ester (S. R. Ohlsen, et al.,
J. Chem. Soc.
(C), 1632-1633 (1971); G. Ya. Kondrat'eva, et al.,
Proc. of the Academy of Sciences, USSR
(
Chem.
), 200, 862-864 (1971)); and (3) oxidative addition of ethyl formylacetate with vinyl acetate (E. Baciocchi, et al.,
Synthetic Communications,
18, 1841-1846 (1988)). These processes suffer from the use of expensive and/or hazardous starting materials and low yields.
F. Effenberger, et al.,
Chem. Ber.,
115, 2766-2782 (1982) and M. Hojo, et al.,
Synthesis,
1016-1017 (1986) describe the trichloroacetylation and trifluoroacetylation of 2,3-dihydrofuran to produce 2,3-dihydro-4-trichloroacetylfuran and 2,3-dihydro-4-trifluoroacetylfuran in good yield. These trihalomethylketone intermediates can be hydrolyzed to yield 2,3-dihydro-4-furoic acid (M. Hojo, et al.,
Synthesis,
1016-1017 (1986); N. Zanatta, et al.,
J. Heterocyclic Chem.,
34, 509-513 (1997)). P. Maynard-Faure, et al.,
Tetrahedron Letters,
39, 2315-2318 (1998) have shown that the trichloromethylketone intermediates can be converted into their esters, i.e., alkyl 2,3-dihydro-4-furoates, by treatment with an alcohol and potassium carbonate.
Methyl 3-furoate has been produced in 18% yield by the bromination of methyl 2,3-dihydro-4-furoate with N-bromosuccinimide followed by heating with 50% aqueous potassium hydroxide (J. T. Wrobel, et al.,
Rocz. Chem.,
40, 1005-1018 (1966)). Methyl and ethyl 2,3-dihydro-4-furoate have been brominated with bromine to give methyl and ethyl 2,3-dibromo-tetrahydro-3-furoate (W. Hasenbrink,
Liebigs Ann. Chem.,
468-476 (1974)). These dibromides can be dehydrobrominated to produce methyl and ethyl 3-furoate but the yield is low and side-products require separation.
BRIEF SUMMARY OF THE INVENTION
An efficient, two-step process for the preparation of alkyl 3-furoates from 4-acyl-2,3-dihydrofurans has been developed. The present invention provides a process for preparing a compound having the formula:
which comprises the steps of:
(1) contacting a compound having the formula:
with a halogenating agent in the presence of an alkanol to obtain an intermediate compound having the formula:
and
(2) contacting intermediate compound (III) with a strong base to produce compound (I) provided that step (2) is carried out in the presence of a source of alkoxide when R
2
is perhaloalkyl; wherein R
1
is alkyl; R
2
is perhaloalkyl or alkoxy; R
3
is alkyl; and X is halogen. The intermediate compounds of formula (III) are novel compositions of matter. If desired, 3-furoic acid can be obtained from ester (I) by hydrolysis. The alkyl 3-furoates obtained in accordance with the process of the present invention are useful for the production of pharmaceutical products (see for example the preparation of an anti-inflammatory agent by D. H. Williams and D. John Faulkner,
Tetrahedron,
52, 4245-4256 (1996)). Ethyl 3-furoate has found utility as a marine and fresh water antifoulant in coating compositions (U.S. Pat. No. 5,259,701).
DETAILED DESCRIPTION
The starting material for the process of the present invention is a 4-acyl-2,3-dihydrofuran of formula (II). Compounds (II) wherein R
2
is a perhaloalkyl group can be prepared according to known procedures such as those described by F. Effenberger, et al.,
Chem. Ber.,
115, 2766-2782 (1982) and M. Hojo, et al.,
Synthesis,
1016-1017 (1986). The perhaloalkyl group may have up to about 4 carbon atoms and the halo substitutents may be selected from chloro, bromo, iodo and fluoro. The perhaloalkyl group which R
2
may represent most preferably is trichloromethyl. It may be possible to form the perhaloalkyl group during the first step of the process of my invention wherein the starting material is contacted with a halogenating agent. For example, 4-(dichloroacetyl)-2,3-dihydrofuran may be converted by a brominating agent to a 2-alkoxy-3-bromo-3-(bromo-dichloroacetyl) tetrahydrofuran intermediate compound.
The trihaloacetyl group (—C(O)CX
3
) is useful in organic synthesis because it behaves much as an carboxylic acid chloride, i.e., it may be hydrolyzed to the carboxylic acid in what is known as the “haloform reaction” (R. C. Fuson, B. A.
Bull, Chem. Rev.,
15, 275(1934)) or converted to an ester by base-catalyzed reaction with an alkanol. A trihalomethane (haloform) is the by-product of this reaction. Normally in the haloform reaction a methyl ketone is halogenated under basic conditions resulting in formation of an intermediate trihalomethyl ketone which hydrolyzes to a carboxylic acid and a trihalomethane. The hydrolysis reaction is known where the attached halogens are fluorine, chlorine, bromine and/or iodine. It is not necessary that all three halogens of the trihalomethyl ketone be the same. Perhaloalkanoyl groups containing more than 2 carbon atoms similarly are useful in the haloform reaction. A convenient and high yield process to prepare these starting materials is via the acylation of 2,3-dihydrofuran. For example, as already discussed, 2,3-dihydro-4-trichloroacetylfuran [Compound (II), R
2
═CCl
3
] is produced in high yield and selectivity by
Blake Michael J.
D'Souza Andrea
Eastman Chemical Company
Gwinnell Harry J.
McKane Joseph K.
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