Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2002-09-12
2003-09-02
Killos, Paul J. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
Reexamination Certificate
active
06613935
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a process for producing 1-acyl-1-cyclopropanecarboxylate derivatives from &bgr;-ketoester derivatives. The 1-acyl-1-cyclopropanecarboxylate derivatives are useful as, for example, pharmaceutical intermediates.
2. Description of the Related Art
Conventionally, 1-acyl-1-cyclopropanecarboxylate derivatives have been produced by, for example, a process disclosed in Japanese Unexamined Patent Application Publication No. 11-240867 in which ethyl acetoacetate is allowed to react with 1,2-dibromoethane in the presence of potassium carbonate to thereby yield a 1-acyl-1-cyclopropanecarboxylate. However, 1,2-dibromoethane used in this process is highly toxic, is expensive and cannot significantly obtained in large quantity.
Alternatively, Russ. Chem. Bl., 43, 1, 84-88, (1994) discloses a process in which a 1-acyl-1-cyclopropanecarboxylate derivative is obtained by electrolysis using 1,2-dichloroethane. However, this process requires special facilities for electrolysis and is low in productivity.
SUMMARY OF THE INVENTION
Accordingly, an object of the present invention is to provide a process for efficiently producing 1-acyl-1-cyclopropanecarboxylate derivatives at low cost. Such 1-acyl-1-cyclopropanecarboxylate derivatives are useful as pharmaceutical intermediates.
After intensive investigations to achieve the above and other objects, the present inventors have found that a corresponding 1-acyl-1-cyclopropanecarboxylate derivative can easily be produced by allowing a &bgr;-ketoester derivative such as an acetoacetate derivative to react with 1,2-dichloroethane that is readily available at low cost.
Specifically, the present invention provides a process for producing a 1-acyl-1-cyclopropanecarboxylate derivative. The process includes the step of allowing a &bgr;-ketoester derivative represented by following Formula (1):
wherein R
1
is a hydrogen atom or a hydrocarbon group; and R
2
is a hydrocarbon group, to react with 1,2-dichioroethane to thereby yield a 1-acyl-1-cyclopropanecarboxylate derivative represented by following Formula (2):
wherein R
1
and R
2
have the same meanings as defined above.
According to the present invention, 1-acyl-1-cyclopropanecarboxylate derivatives which are useful as, for example, pharmaceutical intermediates can efficiently be produced at low cost.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
In the &bgr;-ketoester derivatives represented by Formula (1), R
1
is a hydrogen atom or a hydrocarbon group, and R
2
is a hydrocarbon group.
Such hydrocarbon groups in R
1
and R
2
include aliphatic hydrocarbon groups, alicyclic hydrocarbon groups, aromatic hydrocarbon groups, and hydrocarbon groups each comprising a plurality of these groups combined with each other.
The aliphatic hydrocarbon groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, hexyl, decyl, dodecyl, and other alkyl groups each containing from about 1 to about 10, and preferably from about 1 to about 4 carbon atoms; vinyl, allyl, 1-butenyl, and other alkenyl groups each containing from about 2 to about 10, and preferably from about 2 to about 4 carbon atoms; ethynyl, propynyl, and other alkynyl groups each containing from about 2 to about 10, and preferably from about 2 to about 4 carbon atoms.
The alicyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, and other cycloalkyl groups each containing from about 3 to about 20, preferably from about 3 to about 15, and more preferably from about 5 to about 8 members; cyclopentenyl, cyclohexenyl, and other cycloalkenyl groups each containing from about 3 to about 20, preferably from about 3 to about 15, and more preferably from about 5 to about 8 members.
The aromatic hydrocarbon groups include, but are not limited to, phenyl, naphthyl, and other aromatic hydrocarbon groups each containing from about 6 to about 14, and preferably from about 6 to about 10 carbon atoms.
Hydrocarbon groups each comprising an aliphatic hydrocarbon group and an alicyclic hydrocarbon group combined with each other include, but are not limited to, cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexylethyl, and other cycloalkyl-alkyl groups such as C
3
-C
20
cycloalkyl-C
1
-C
4
alkyl groups.
Hydrocarbon groups each comprising an aliphatic hydrocarbon group and an aromatic hydrocarbon group combined with each other include, but are not limited to, aralkyl groups (e.g., C
7
-C
18
aralkyl groups), and alkyl-substituted aryl groups (e.g., phenyl or naphthyl group having from about one to about four C
1
-C
4
alkyl groups substituted thereon).
In the present invention, R
1
is preferably a C
1
-C
4
aliphatic hydrocarbon group, of which methyl group is typically preferred. The substituent R
2
is preferably a C
1
-C
4
aliphatic hydrocarbon group.
The amount of 1,2-dichloroethane is generally equal to or more than 0.8 mole (e.g., from about 0.8 to about 3 moles) per mole of &bgr;-ketoester derivative represented by Formula (1).
A reaction is generally performed in the coexistence of a base. Such bases include inorganic bases and organic bases. Such inorganic bases include, but are not limited to, sodium carbonate, potassium carbonate, and other alkali metal carbonates; sodium hydrogencarbonate, potassium hydrogencarbonate, and other alkali metal hydrogencarbonates; sodium hydroxide, potassium hydroxide, and other alkali metal hydroxides; sodium hydride, potassium hydride, and other alkali metal hydrides; magnesium carbonate, calcium carbonate, and other alkaline earth metal carbonates; magnesium hydroxide, calcium hydroxide, and other alkaline earth metal hydroxides. Such organic bases include, but are not limited to, triethylamine, and other amines; and pyridine, and other nitrogen-containing heterocyclic compounds. Among these bases, alkali metal carbonates are preferred, of which potassium carbonate is typically preferred. Each of these bases can be used alone or in combination.
The amount of the base is set depending on its type and is generally from about 0.5 to about 4 moles, and preferably from about 0.6 to about 2.5 moles per mole of the &bgr;-ketoester derivative represented by Formula (1). For example, when an alkali metal carbonate is used as the base, the amount is generally from about 0.5 to about 2 moles, and preferably from about 0.6 to about 1.5 moles per mole of the &bgr;-ketoester derivative. When an alkali metal hydroxide is used as the base, the amount is generally from about 2 to about 4 moles, and preferably from about 2 to about 2.5 moles per mole of the &bgr;-ketoester derivative.
The reaction is performed in the presence of, or in the absence of, a solvent. Such solvents are not specifically limited, as long as they do not adversely affect the progress of the reaction. Examples of the solvents include N,N-dimethylformamide, N,N-dimethyiacetamide, and other amides; benzonitrile, and other nitriles; diethyl ether, t-butyl methyl ether, dimethoxyethane, diethoxyethane, tetrahydrofuran, and other chain or cyclic ethers. Among them, preference is given to N,N-dimethylformamide, N,N-dimethylacetamide, and other amides; dimethoxyethane, diethoxyethane, and other glycol ethers, and other polar solvents. Each of these solvents can be used alone or in combination. An excess amount of 1,2-dichloroethane (a reacting agent) can be used as a solvent.
When plural types of solvents are used in combination, the ratio of these solvents may significantly affect the reaction time and yield in some cases. More specifically, when 1,2-dichloroethane and a polar solvent such as N,N-dimethylacetamide are used in combination, the reaction time is prolonged if the ratio of 1,2-dichloroethane to the polar solvent is excessively large. In contrast, the reaction time is shortened but the yield is decreased if the ratio of the polar solvent such as N,N-dimethylformamide to 1,2-dichloroethane is excessively large. Accordingly, the weight ratio of 1,2-dichloroethane to the pola
Ikura Kiyoshi
Pan Li Rui
Tanaka Hiroki
Daicel Chemical Industries Ltd.
Killos Paul J.
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