Process for preparing substituted acetals of malondialdehyde

Details Process for preparing substituted acetals of malondialdehyde Process for preparing substituted acetals of malondialdehyde

2000-01-28

2002-05-28

Keys, Rosalynd (Department: 1621)

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

Organic compounds

Nitriles

C560S186000, C560S187000

Reexamination Certificate

active

06395920

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a process for preparing 2-substituted and 2,2-disubstituted acetals of malondialdehyde.
BACKGROUND OF THE INVENTION
Substituted acetals of malondialdehyde of the general formula (I):
in which R
1
, R
2
, R
3
and R
4
are the same or different alkyl, cycloalkyl, aralkyl or aryl groups with up to 12 carbon atoms and in which R
5
and R
6
represent independently of each other H, alkyl, cycloalkyl, aralkyl, aryl, COOH, COONa, COOR, CHO, C(OR)
2
, CN, CONH
2
, CONHR, or CONR
2
, with the proviso that R
5
and R
6
cannot both be H, alkyl, cycloalkyl or aralkyl, are valuable building blocks for the synthesis of heterocycles.
The compounds of general formula I can be easily hydrolyzed to the respective 2-substituted and 2,2-disubstituted free malondialdehydes of general formula II where R
5
and R
6
are as described above:
Accordingly, they have to be regarded as precursors for any product the synthesis of which requires the use of the free aldehydes of general formula II.
While the substituted malondialdehydes of general formula II are normally more stable toward polymerization than the unsubstituted malondialdehyde, they are thermally unstable as indicated, for example, by losses of 41% on distillation of ethoxycarbonyl malondialdehyde under very mild conditions (Bertz, S. H., Dabbagh, G., Cotte, J. Org. Chem. 1982, 47, 2216). Since handling-hazards and product losses, as well as a potential contamination of the reaction mixtures with polymeric material result from using the compounds of general formula II for the synthesis of heterocycles, and since the compounds of general formula I can be stored even above room temperature for extended periods of time, it is advantageous to generate the substituted malondialdehydes of general formula II from the malondialdehyde acetals of general formula I either just prior to their use or, preferably, in situ, especially under commercial conditions.
The compound 2-ethoxycarbonyl-malondialdehyde has found an especially broad range of applications, for example, in the synthesis of pyridine derivatives (JP 61,289,077), pyrimidines (Schenone, P., Sansebastiano, L., Mosti, L., J.
Heterocycl. Chem
. 1990, 27 (2), 295), pyrazoles (Holzer, W., Seiringer, G., J.
Heterocycl. Chem
. 1993, 30, 865), isoxazoles (Kusumi, T. et al.,
Tetrahedron Letters
22 (1981), 36, 3451), phenolic compounds (Prelog, V., Wuersch, J., Koenigsbacher, K., Helv. Chim. Acta 1951, 34, 258; Bertz, S. H., Dabbagh, G., Angew. Chem. Int. Ed. EngI. 1982, 21, 306) and pharmaceuticals (U.S. Pat. No. 4,808,595; Genin, M., J. et al. J. Med. Chem. 1998, 41, 5144). This broad utility is at least partially due to the availability of this compound by the condensation of. 3,3-diethoxypropionate with ethyl formate in the presence of base (Bertz, S. H., Dabbagh, G., Cotte, P., J. Org. Chem. 1982, 47, 2216). Besides providing the free aldehyde instead of a diacetal, this approach suffers from several major drawbacks, such as the expense of 3,3-diethoxypropionate, the difficulty encountered in handling NaH, which is the starting material and the formation of wastewater.
Ethyl-2-dimethoxymethyl-3,3-dimethoxy-propionate can be prepared by the reaction of malondialdehyde bis-dimethylacetal with carbonochloridic acid ethyl ester. However, this approach has to be regarded as being solely a laboratory synthesis since it requires the handling of such hazardous materials as potassium and diethylether. Further, the use of liquid ammonia as the reaction medium is very costly under commercial conditions.
The situation with respect to other 2-substituted malondialdehyde-derivatives is similar. Whereas, for example, 2-cyano-3-dimethylamino-acrolein is a stable precursor for 2-cyano-malondialdehyde, its synthesis via Vilsmeier-formylation of acetonitrile (Reichardt, G., Kerrner, W. D.,
Synthesis
1970, 538) leads to excessive formation of phosphorous-contaminated wastewater besides which the yield is only 32% , referred to DMF. Also, this approach is fairly specific and gives dimethylamine on hydrolysis of the malondialdehyde-precursor.
While there are some applications for the compounds of general formula I, such as the synthesis of substituted pyridines (Benoit, R. et al.,
J. Heterocycl. Chem
. 1989, 26, 1595), their use is largely limited by their availability. Thus, a need exists for a general process that affords 2-substituted and 2,2-disubstituted acetals of malondialdehydes of general formula I from easily available starting materials without the drawback of requiring several steps and/or the stoichiometric formation of salts and/or the formation of excessive amounts of wastewater.
By the process of the present invention ready access is provided to the compounds of general formula I by the addition of ortho formates to 2-substituted and 2,2-disubstituted vinylethers, thereby avoiding the above-noted disadvantages.
SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of 2-substituted and 2,2-disubstituted acetals of malondialdehyde of general formula I:
in which R
1
, R
2
, R
3
and R
4
are the same or different alkyl groups, cycloaliryl groups, aralkyl groups or aryl groups with up to 12 carbon atoms and in which R
5
and R
6
represent independently of each other H, alkyl, cycloalkyl, aralkyl, aryl, COOH, COONa, COOR, CHO, C(OR)
2
, CN, CONH
2
, CONHR or CONR
2
, with the proviso that R
5
and R
6
cannot both be H, alkyl, cycloalkyl or aralkyl, by reacting compounds of general formula III:
and ortho formates of general formula IV:
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for preparing 2-substituted and 2,2-disubstituted acetals of malondialdehyde of general formula I:
in which R
1
, R
2
, R
3
and R
4
are the same or different alkyl groups, cycloalkyl groups, aralkyl groups or aryl groups with up to 12 carbon atoms and in which R
5
and R
6
represent independently of each other H, alkyl, cycloalkyl, aralkyl, aryl, COOH, COONa, COOR, CN, CHO, C(OR)
2
, CONH
2
, CONHR, or CONR
2
, with the proviso that R
5
and R
6
cannot both be H, alkyl, cycloalkyl or aralkyl.
Upon hydrolysis of the compounds of general formula I to the free aldehydes, it is normally advantageous to avoid the generation of a mixture of alcohols. In a preferred embodiment of the process of the invention, the groups R
1
, R
2
, R
3
and R
4
are therefore identical.
It has been found that this is achieved in a simple manner and that 2-substituted and 2,2-disubstituted acetals of malondialdehyde of general formula I are obtained advantageously when a vinylether of general formula III:
in which R
1
, R
5
and R
6
are as defined above, is reacted with an ortho formate of general formula IV:
in which R
2
, R
3
and R
4
are as defined above.
In the absence of a catalyst, the above reaction is normally extremely slow. It is, therefore, advantageous to conduct the reaction in the presence of a catalyst. Acidic catalysts, especially strong Lewis acids, give superior reactivities and selectivities. Examples of such catalysts are SnCl
4
, SnCl
3
Ph, AlCl
3
, BBr
3
, SbF
5
, and ZnCl
2
, FeCl
3
as well as BF
3
have been found to be especially selective and reactive homogeneous catalysts. Since homogeneous, as well as heterogeneous catalysts, such as acidic Al
2
O
3
or montmorillonites, have been found to increase the reaction rate, in a preferred embodiment of the process according to the present invention, the reaction is carried out continuously using a fixed catalyst bed. A fixed bed catalyst does not have to comprise a single compound or a single mineral. The use of homogeneous catalysts, especially Lewis acids like FeCl
3
on a suitable support, such as SiO
2
, and commercially available catalysts, such as Envirocat EPZG sold by Contract Chemicals Ltd. of Prescot, Merceyside, United Kingdom have been found to produce advantages with respect to reactivities and handling properties.
The amount of catalyst required to give desirable reaction rates has been found to cover a broad range and depends

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