Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
1998-11-24
2001-07-17
Geist, Gary (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S124000, C560S127000
Reexamination Certificate
active
06262298
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to a process for the C-monoalkylation or C-dialkylation of a dialkyl malonate with an alkyl halide or an alkylene dihalide having vicinal halogen atoms and potassium carbonate (potash) as the hydrogen halide acceptor.
2. Description of Related Art
DE 43 26 917 describes a process for the preparation of cyclopropane-1,1-dicarboxylic esters from dialkyl malonates and alkylene dihalides having vicinal halogen atoms (referred to below as alkylene dihalides for short) with potassium carbonate as a hydrogen halide acceptor and dimethylformamide or dimethylacetamide as a solvent. In the process, a) alkylene dichlorides are employed, b) potassium carbonate having fine particle fractions of 85% or more smaller than 0.1 mm and 70% or more smaller than 0.05 mm is used, c) the water of reaction is distilled off azeotropically during the reaction, d) the reaction temperature is brought to 90 to 160° C. and e) the molar ratio of dialkyl malonate to alkylene dichloride to potassium carbonate is chosen as 1:(2.5-3.5):(1.0-1.4).
This process constitutes a significant improvement over previously known procedures. Thus, even the cheaply available alkylene dichlorides give yields of more than 80% of theory, which could not be achieved according to D.A. White, Synthetic Communications, 1977, page 599, even with the corresponding alkylene dibromides. Instead of potassium bromide which is difficult to dispose of, potassium chloride, which can be used for the electrolytic preparation of potassium hydroxide, is obtained. The space-time yields for reaction times of from 5 to 6 hours are considerably better than in the process of D.A. White, loc. cit., which requires 22 hours, and in the procedure according to J. Heiszman et al., Synthesis Communications 1987, page 738, in which alkylene dichlorides are employed with benzene as a solvent, a phase-transfer catalyst is used and the reaction time is 20 hours.
There is a need for a process for C-alkylating or dialkyl malonate where the process provides an enhanced conversion of dialkyl malonate relative to conventional processes.
SUMMARY OF THE INVENTION
Accordingly, one object of the present convention is to provide a novel process for C-alkylating dialkly malonates in which the conversation of dialkyl malonate is improved relative to conventional processes. In particular, it has now been found that dialkyl malonates can be advantageously C-alkylated if a dialkyl malonate is reacted with an alkyl halide or an alkylene dihalide in the presence of potassium carbonate in an inert solvent and a phase-transfer catalyst is not added until from about 50% to about 80% of the dialkyl malonate has reacted.
DETAILED DESCRIPTION OF THE INVENTION
In the process of the present invention, if an alkyl halide and an unsubstituted dialkyl malonate are used, the monosubstituted or the disubstituted derivative is obtained, depending on the molar ratio of dialkyl malonate to alkyl halide to potassium carbonate. For the preparation of C-monosubstituted dialkyl malonates, the substances are advantageously used in a molar ratio of 1:(1.5-3.0):(0.4-0.6), in particular of 1:(2.0-2.5):(0.45-0.5) takes place according to the equation
Here, R and R′ denotes an alkyl radical. Hal denotes a halide. For the preparation of dialkylated derivatives, a molar ratio of 1:(2.5-4.5):(1.0-1.5), in particular of 1:(2.5-3.0):(1.1-1.3), is advantageously chosen. A special case of the dialkylated derivatives comprises the cyclopropane compounds which are obtained if an alkylene dihalide or 1,2-alkylene dihalide is used as a starting material:
Here, R, R∝ and R″ independently each denote an alkyl radical or hydrogen. In this case, a molar ratio of 1:(2.5-3.5):(1.0-1.4), advantageously of 1:(2.5-3.0):(1.0-1.4), is advisable.
C-Monoalkylated dialkyl malonates can be converted by the process according to the invention into dialkyl-substituted derivatives. Disubstituted dialkyl malonates having different alkyl substituents can be prepared in this manner.
Surprisingly, in the process according to the invention, the reaction times can be shortened considerably—to 3 hours in the case of the stated process for the preparation of cyclopropane-1,1-dicarboxylic esters—and the space-time yields correspondingly increased.
Many of the dialkyl malonates used as starting materials are available in commercial quantities. Dialkyl malonates having C
1-4
-alkyl radicals, such as dimethyl malonate (DMM) and diethyl malonate (DEM), which are preferred, and diisopropyl malonate and di-n-butyl malonate, may be mentioned as examples of suitable dialkyl malonates.
Preferred alkyl halides, including, for example, alkylene dihalides or 1,2-alkylene dihalides, are the chlorides. Suitable alkyl chlorides and alkylene dichlorides have in general up to 12, in particular up to 6, carbon atoms. For example, methyl chloride (can be reacted only under superatmospheric pressure), ethyl chloride, isopropyl chloride, allyl chloride, isoamyl chloride, 2-chlorohexane, 1-chlorooctane, 1,2-dichloroethane (i.e., ethylene dichloride, EDC), 1,2-dichloropropane, 2,3-dichlorobutane and 1,2-dichlorocyclohexane may be mentioned specifically.
The potassium carbonate used is the usual product, which is free of water of crystallization and which has been brought to a fine particle size by milling, for example in ball mills or pinned-disk mills. A potassium carbonate having fine particle fractions of 85% or more smaller than 0.1 mm and 70% or more smaller than 0.05 mm is particularly suitable.
Suitable inert solvents which are expediently concomitantly used are in particular dimethylformamide (DMF), dimethylacetamide (DMA) and N-methyl-2-pyrrolidone (NMP). dimethylformamide (DMF), dimethylacetamide (DMA), and N-methyl-2-pyrrolidone (NMP). They are expediently used in 3 to 4 times the amount by weight, based on the weight of the dialkyl malonate.
The water of reaction is expediently removed from the reaction mixture with the aid of an entraining agent. If dialkylated malonic esters are prepared, excess alkyl halide or alkylene dihalide can be used as entraining agent. This is also possible in the conversion of alkyl halides to monoalkylated derivatives, by using, for example, stoichiometric amounts of alkyl halide and recycling the alkyl halide distilled off with the water to the reaction after condensation and phase separation. Alternatively, it is also possible to add one of the conventional inert entraining agents, e.g. toluene.
An important feature of the process according to the invention is that the reaction can be carried out to a dialkyl malonate conversion of from 50 to 80% and thereafter a phase-transfer catalyst is added and the reaction is completed.
The phase-transfer catalyst facilitates the interaction of the reactants present in the liquid phase with the solid potassium carbonate, as is evident from the increased evolution of carbon dioxide, which is triggered by the addition of the phase-transfer catalyst. Suitable phase transfer catalysts are, for example, quaternary ammonium salts, such as tetraalkylammonium salts, advantageously having C
1
- to C
8
-alkyl radicals and in particular having C
1
- to C
4
-alkyl radicals, and the corresponding ammonium hydroxides, such as a tetraalkylammonium hydroxide such as tetra-n-butylammonium hydroxide. The salts may be, for example, halides, hydrogen sulfates or sulfates. For example, tetrabutylammonium bromide (TBAB), tetra-n-butylammonium bromide, tetrabutylammonium hydrogen sulfate, tetra-n-butylammonium hydrogen sulfate, tetraoctylammonium bromide, benzyltriethylammonium chloride and methyltrioctylammonium chloride may be mentioned as typical members of these classes of substance. The corresponding phosphonium compounds, such as a tetraalkylphosphonium salt, a tetraalkylphosphonium hydroxide, tetra-n-butylphosphonium hydroxide and tetra-n-butylphosphonium bromide, are also suitable. Other phase-transfer catalysts which may be used in the present invention are crown ethers, in particular 18-crown-6. Ph
Metz Josef
Osterholt Clemens
Deemie Robert W.
Geist Gary
Huels Aktiengesellschaft
Oblon & Spivak, McClelland, Maier & Neustadt P.C.
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