Substituted propenoates and processes for the preparation...

Details Substituted propenoates and processes for the preparation... Substituted propenoates and processes for the preparation...

2000-01-28

2002-09-17

Padmanabhan, Sreeni (Department: 1623)

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

Organic compounds

Carboxylic acid esters

C560S210000, C560S130000, C560S183000, C560S186000

Reexamination Certificate

active

06452042

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to substituted propenoates and processes for the preparation thereof.
DESCRIPTION OF THE BACKGROUND
Substituted propenoates of the 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 constitute valuable building blocks in the synthesis of, for example, heterocycles such as pyrazoles, pyrimidines, and isoxazoles.
As demonstrated in a co-pending, commonly assigned patent application, filed on even date herewith, entitled “Process for Preparing Substituted Acetals of Malondialdehyde”, the disclosure of which is incorporated herein by reference, the use of malondialdehyde acetals of general formula (II)
in which R
1
, R
2
, R
3
, R
4
and R
5
are the same or different alkyl groups, cycloalkyl groups, aralkyl groups or aryl groups with up to 12 carbon atoms for the preparation of heterocycles is advantageous over the use of the free aldehydes of general formula (III):
in which R
1
is an alkyl group, cycloalkyl group, aralkyl group or aryl group, with up to 12 carbon atoms.
However, it has been found that the compounds of general formula II normally are less reactive than the free aldehydes of general formula III. In fact, upon use of the compounds of general formula II for the preparation of heterocycles, it was found that the addition of water to the reaction mixture can be advantageous. Most likely, this water-addition leads to hydrolysis or partial hydrolysis of the diacetals to the free aldehydes, which then react to form the heterocycles. The addition of water to the reaction mixtures in order to activate the compounds of general formula II is often undesirable, for example, with respect to a potential hydrolysis of the ester-group COOR
1
. Thus, a need exists for easily accessible, thermally stable compounds that can be used as substitutes for the compounds of general formula II, provided, however, that these compounds are more reactive, for example, in the synthesis of heterocycles, as well as a process for the preparation of these compounds.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide substituted propenoates 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 as a new class of building blocks, as well as, processes for the preparation thereof.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Substituted propenoates of the 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 constitute valuable building blocks in the synthesis of, for example, heterocycles, such as pyrazoles, pyrimidines, and isoxazoles. They can be used advantageously as substitutes for the compounds of general formula II and III. While the compounds of general formula II are easily accessible from orthoesters and substituted acrylates, as disclosed in a co-pending application of even date entitled “Process for Preparing Substituted Acetals of Malondialdehyde”, they were generally found to be less reactive than the compounds of general formula III. As will be shown later, the compounds of general formula I combine the advantages of easy accessibility, low formation of salt waste, and high thermal stability with the added advantage of a higher reactivity as compared to the compounds of general formula II. The increased reactivity results from the presence of the enol-ether structural element in the compounds of general formula I. The preparation of heterocycles from the compounds of general formula I, instead of the compounds of general formula II, has the additional advantage of leading to the formation of smaller amounts of alcohols, i.e., no R
5
-OH is formed.
2-ethoxycarbonyl-malondialdehyde in particular has found a 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. Engl
. 1982, 21, 306) and pharmaceuticals (U.S. Pat. No. 4,808,595; Genin, M.,
J. et al. J. Med. Chem
. 1998, 41, 5144), which is, at least, partially due to the availability of this compound by the condensation of ethyl-3,3-diethoxypropionate with ethyl formate in the presence of base (Bertz, S. H., Dabbagh, G., Cotte, P.,
J. Org. Chem
. 1982, 47, 2216). However, besides providing the free aldehyde instead of a diacetal, this approach suffers from several major drawbacks such as expensive (ethyl-3,3-diethoxypropionate) or difficult to handle (NaH) starting materials and the formation of wastewater.
Especially, in the use of the compounds of general formula I for the preparation of heterocycles, the alcohols of general formula R
1
OH and/or R
2
OH and/or R
3
OH and/or R
4
OH are liberated. In order to achieve high space-time-yields and to facilitate the isolation procedures for the compounds of general formula I, it is generally desirable to limit the molecular weight of the compounds of general formula I. Consequently, those compounds where R
1
, R
2
, R
3
, and R
4
=methyl and ethyl are especially preferred.
It has been found that the compounds of general formula I can advantageously be reacted with reactants, such as hydroxylamines, hydroxylamine salts, hydrazine, hydrazine salts, formamide, amidines, amidine salts, guanidines, guanidine salts, aminoguanidines, aminoguanidine salts, alkyl-3-aminoacrylates, cycloalkyl-3-aminoacrylates, aryl-3-aminoacrylates, aralkyl-3-aminoacrylates, nitroguanidine, nitroguanidine salts, O-alkyl-isoureas and their salts, O-cycloalkyl-isoureas and their salts, O-aralkyl-isoureas and their salts, O-aryl-isoureas and their salts, S-alkyl-isothioureas, S-cycloalkyl-isothioureas, S-aralkyl-isothioureas, S-aryl-isothioureas respective S-alkyl-isothiouronium salts, S-cycloalkyl-isothiouronium salts, S-aralkyl-isothiouronium salts, S-aryl-isothiouronium salts, thiourea, and urea to form a heterocycle.
The compounds of general formula I were previously unknown. Their production on a commercial scale requires a process or processes that gives high yields based on easily accessible starting materials without the formation of excessive amounts of salt waste. It has been found that this is achieved in a simple manner by the elimination of an alcohol of general formula R
5
OH from the compounds of general formula II. Several commercially viable processes were identified that allow for the elimination of an alcohol R
5
OH from the compounds of general formula II. The simplest process comprises heating the compounds of general formula II in the presence of an appropriate catalyst, while removing the formed alcohol by distillation, such as vacuum distillation or azeotropic distillation.
Acidic catalysts, preferably mild Lewis acids, especially preferred mildly Lewis acidic heterogeneous catalysts are used. Examples of such catalysts are salts, such as NH
4
Cl, (NH
4
)
2
SO
4
, NR
3
HCl, NR
3
HCl, transition metal salts, such as Zn(acac)
2
, ZnSO
4
, Fe(OAc)
2
, ZnCl
2
, Zn(OAc)
2
, acetic acid, aluminum oxide, zinc oxide, zeolites, montmorillonites, or metal-exchanged zeolites and montmorillonites.
The amount of catalyst required to give reasonable reaction rates was found to cover a broad range and depended to a great extent on the nature of the catalyst. Normally, catalyst-concentrations below 0.000001 w/w-%, with reference to the compounds of general formula II, led to unacceptably long reaction-times, even with the use of highly reactive Lewis acids. On the other hand, especially if the process according to the invention

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