Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2000-05-08
2002-07-23
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S038000
Reexamination Certificate
active
06423866
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to a method of synthesizing lower alkyl 3-amino-crotonates, which are substituted at the C-4 atom by halogen and at the amino group by 1 or 2 hydrogen atoms and/or 1 or 2 C
1
to C
3
alkyl groups or 1 or 2 aryl groups.
Lower alkyl 3-amino-crotonates, substituted by halogen at the C-4 atom, especially lower alkyl 3-amino-4,4,4-trifluorocrotonates are used as building blocks in chemical synthesis. They can be used, for example, for synthesizing herbicidal uracil derivatives, as disclosed in U.S. Pat. No. 5,399,543.
A method of synthesizing such compounds is given by W. F. Goure in
J. Heterocyclic Chem.
30 (1993), pages 71 to 80 and especially on page 75. Anhydrous ammonia is passed for a period of 1.5 hours at a temperature of 75° to 80° C. through methyl 4,4,4-trifluoroacetoacetate. Subsequently, the reaction mixture is kept for a further 3 hours at a temperature of 100° C. and then cooled to ambient temperature, taken up in diethyl ether, dried, concentrated and subjected to a bulb tube distillation. The yield was 59% of the theoretical.
The thermolysis of the ammonium salt in the presence of acetic acid and ethanol is described in the Japanese patent application JP 6/321877. The European patent application EP-A-0 808 826 discloses the synthesis of trihalogen crotonates using ammonium salts as a source of amine. The ammonium salt of the ester is not formed. The formation of esters of aminocrotonic acids from NH3 and esters of acetoacetic acid or esters of trifluoroacetoacetic acid with and without solvents is disclosed in Houben-Weyl, Methods of Organic Chemistry, Volumn XI/I (1957), pages 170-175, and by Pashkevich et al. in Bull. Acad. Sci. USSR Div. Chem. Sci 35 (1986), pages 1438-1442.
It is an object of the present invention to provide a method for synthesizing crotonates, which are halogen-substituted at the C-4 atom and selected from the group comprising lower alkyl esters of 3-amino-4,4,4-trifluoro-crotonates and lower alkyl 3-amino-4,4-difluoro-4-chloro-crotonates and lower alkyl 3-amino-4,4-difluoro-crotonates, with which method these products are obtained in high yield with a high degree of purity. This objective is accomplished by the method of the present invention.
The inventive method of synthesizing crotonates, which are halogen-substituted at the C-4 atom and selected from the group consisting of lower alkyl 3-amino-4,4,4-trifluoro-crotonates, lower alkyl 3-amino-4,4-difluoro-4-chloro-crotonates and lower alkyl 3-amino-4,4-difluorocrotonates, the amino group optionally being substituted by 1 or 2 C
1
to C
3
alkyl groups or by aryl groups, and lower alkyl denotes methyl, ethyl, n-propyl, and i-propyl, envisions the simultaneous formation under thermolytic conditions without addition of an acid, of water and lower alkyl 3-aminocrotonates substituted by halogen at the C-4 atom, the water formed being removed from the reaction mixture, in that a thermolysis reaction is carried out starting from the ammonium salt of the corresponding lower alkyl acetoacetate substituted at the C-4 atom by halogen, and in the presence of an entraining agent for the water formed, or in that, in the absence of a solvent, inert gas is passed through the molten ammonium salt of the lower alkyl acetoacetate substituted at the C-4 atom by halogen and by these means, water formed is removed from the reaction mixture.
Accordingly, the method can be carried out according to several alternative procedures. The first alternative is explained in the following.
This alternative of the inventive method for synthesizing crotonates, which are halogenated at the C-4 atom and are selected from the group comprising lower alkyl 3-amino-4,4,4-trifluorocrotonates, lower alkyl 3-amino-4,4-difluoro-4-chlorocrotonates and lower alkyl 3-amino-4,4-difluorocrotonates, in which the amino group optionally may be substituted by 1 or 2 C
1
to C
3
alkyl groups or by aryl groups, is characterized in that the appropriate ammonium salt of the lower alkyl acetoacetate, substituted at the C-4 atom by halogen, is thermolyzed in the presence of an entraining agent for the water formed during the thermolysis.
Pursuant to this embodiment, lower alkyl esters of 3-amino-4,4-difluorocrotonate can be synthesized from the ammonium salt (the nitrogen may be substituted especially completely by hydrogen or by hydrogen and 1 or 2 C
1
to C
3
alkyl groups) of the 4,4-difluoroacetoacetate ester. Lower alkyl esters of 3-amino-4,4-difluoro-4-chlorocrotonate are synthesized correspondingly from the salt of the 4,4-difluoro-4-chloroacetoacetate. Lower alkyl esters of 3-amino-4,4,4-trifluorocrotonate are synthesized similarly.
The required esters are commercial products or can be synthesized by the reaction of ketene with trifluoroacetyl chloride, difluorochloroacetyl chloride or difluoroacetyl chloride, followed by an esterification, as described by W. F. Goure,
J. Heterocyclic Chem.
30 (1993), pages 71 to 80 and especially page 72.
The inventive method can be carried out starting from the ammonium salt. For example, the ammonium salt can be synthesized in a first step. It is then thermolyzed in a second step. Pursuant to a different embodiment, the ammonium salt is synthesized in situ and simultaneously thermolyzed. This embodiment can also be carried out continuously.
Preferably, 4,4,4-trifluorocrotonates are synthesized. The invention will be described further with reference to this preferred embodiment.
The following apply generally for all the alternatives of the present invention. A catalyzing agent, such as an acid, is not required and is not added. The amine or ammonia used is added as base and not as a salt, for example, of carboxylic acids. The term “lower alkyl” denotes methyl, ethyl, n-propyl and i-propyl. “Aryl” preferably refers to phenyl.
Preferably, crotonates, which have two hydrogen atoms at the amino group, are synthesized. The synthesis of methyl 3-amino-4,4,4-trifluorocrotonate or ethyl 3-amino-4,4,4-trifluorocrotonate is especially preferred.
Entraining agents are used, which do not enter into undesired reactions with the starting materials or with the products. Aliphatic hydrocarbons, aromatic hydrocarbons or halogenated aliphatic hydrocarbons, for example, are suitable. For example, benzene or toluene can be used as entraining agent. Entraining agents which have a higher density than the water phase that forms and therefore represent the lower phase are especially preferred. Halogenated hydrocarbons, such as trichloroethylene or carbon tetrachloride, are particularly suitable. Entraining agents of higher density extract the ammonium salt, which is present in the lighter water phase in the water separator and, in this way, decrease the loss in yield, especially in the case of products that sublime.
The synthesis is carried out under conditions at which the water-entraining agent boils. For the sake of simplicity, the reaction is carried out at ambient pressure; if so desired, the reaction can, of course, also be carried out at an elevated or a reduced pressure.
Preferably, the temperature of the reaction mixture falls within the range of 80° to 120° C. Naturally, the temperature used also depends on the boiling point of the entraining agent.
When water is no longer collected in the water separator, the entraining agent is removed, for example, by distillation and the remaining crude crotonate is purified by vacuum distillation (for example, the vacuum of a water jet pump). Ethyl 3-amino-4,4,4-trifluorocrotonate distills at a temperature of 55° to 57° C.
Pursuant to a second alternative, which is described in the following, the water of reaction is carried away by an inert gas. For this embodiment of synthesizing lower alkyl 3-aminocrotonates, which are substituted at the C-4 atom by halogen and selected from the group consisting of lower alkyl 3-amino-4,4,4-trifluorocrotonates, lower alkyl 3-amino-4,4-difluorocrotonates and lower alkyl 3-amino-4,4-difluoro-4-chlorocrotonates, provisions are made to start in the absence of a solvent from a molten ammonium
Braun Max
Eichholz Kerstin
Jannssens Francine
Rudolph Werner
Chaudhry Mahreen
Crowell & Moring LLP
Killos Paul J.
SolvaytFlour und Derivate GmbH
LandOfFree
Production of aminohalogencrotonates does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Production of aminohalogencrotonates, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Production of aminohalogencrotonates will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2826203