Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-05-04
2001-11-20
Davis, Zinna Northington (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S291000, C546S323000, C546S326000, C546S327000
Reexamination Certificate
active
06320053
ABSTRACT:
BACKGROUND OF THE INVENTION
Heteroarylcarboxylic amides and esters are suitable intermediates for the preparation of a broad variety of compounds which are useful as agrochemicals or pharmaceuticals. In particular, they are key intermediates in the preparation of herbicidal aryloxyheteroarylcarboxamides which are described, for example, in EP 0 447 004 A or WO 94/27974.
European patent application EP 0 646 566 A suggests the hydrolyzation of trichloromethyl heteroarenes with water in the presence of chlorinated hydrocarbons and a Lewis acid, followed by reaction of the resulting heteroarylcarbonyl chloride with an amine. However, this process causes problems with respect to the rate and the exact equimolar addition of water. Any excess of water will cause hydrolysis of the desired acid chloride compound and therefore reduce the yields. Moreover, the use of chlorinated hydrocarbons is undesirable due to environmental problems, and a large amount of solvent is required. Furthermore, a very long (24 hour) reaction time using water/1,2-dichloroethane is necessary.
It is also known that pyridinecarboxylic acids are reparable by the hydrolysis of the corresponding (trichloromethyl)pyridine compound in a strong acid such as sulfuric acid or nitric acid (U.S. Pat. No. 3,317,549). German patent application DE 28 40 924 discloses a process in which benzotrihalides are treated with concentrated or fumic sulfuric acid. This process yields mixtures of benzoylhalides and halosulfonylbenzoylhalides.
SUMMARY OF THE INVENTION
The present invention provides an effective and efficient process for the preparation of heteroarylcarboxylic amides and esters of formula I
wherein
one or two of the groups A
1
, A
2
, A
3
, A
4
and A
5
represent a nitrogen atom and the other groups each independently represent CR
3
,
Hal represents a halogen atom,
X represents oxygen or NR
2
,
R
1
represents an optionally substituted alkyl, aryl, heteroaryl or cycloalkyl group,
R
2
represents a hydrogen atom or an alkyl group, or
R
1
and R
2
together with the interjacent ring form a heterocyclic group, and
R
3
each independently represent a hydrogen atom or an alkyl group,
which comprises the following steps:
a) heating a mixture consisting essentially of a heteroaryltrichloromethane compound of formula II,
wherein
Hal and A
1
through A
5
are as hereinbefore defined,
and 1.0 to 1.5 equivalents of concentrated sulfuric acid,
b) reacting the intermediate product obtained in step (a) with an amine or alcohol of formula III,
HXR
1
III
wherein X and R
1
are as hereinbefore defined, optionally in the presence of a diluent and/or a base.
It is, therefore, an object of the present invention to provide an efficient new process for the preparation of heteroarylcarboxylic amides and esters in high yield and purity.
Another aspect of the present invention is a process for the preparation of a (hetero)aryloxyheteroaryl-carboxylic amide or ester of formula VI
wherein A
1
through A
5
, R
1
and X are as hereinbefore defined, and R
4
represents an optionally substituted aryl or heteroaryl group, wherein the heteroarylcarboxylic amide or ester of formula I or a salt thereof, is prepared from a trichoromethyl-heteroaromatic compound of formula II and is reacted with an aromatic or heteroaromatic hydroxyl compound of formula VII,
R
4
—OH VII
wherein R
4
is as hereinbefore defined, optionally in the presence of a base.
Other objects and advantages of the present invention will be apparent to those skilled in the art from the following description and the appended claims.
DETAILED DESCRIPTION OF THE INVENTION
The heteroaryltrichloromethane compounds of formula II include pyridines, pyrimidines and pyrazines which are substituted by one trichloromethyl group, one halogen atom and optionally by one to three alkyl groups. The pyridines of formula IIa are preferred:
wherein R
3
represents a hydrogen atom or an alkyl group and Hal represents a halogen atom, preferably a chloro atom; in particular those of formula IIa1:
wherein Hal and R
3
are as hereinbefore defined; most preferred is nitrapyrin (NP), a compound of formula IIa1, in which Hal is Cl and R
3
is H.
In general terms, unless otherwise stated herein, the term “optionally substituted alkyl, aryl, heteroaryl or cycloalkyl group” as used herein with respect to R
1
or R
4
refers to a alkyl, phenyl, pyridine, pyrimidine or a C
3-8
cycloalkyl group optionally substituted by one or more halogen atoms, nitro, cyano, alkyl, preferably C
1-6
alkyl, alkoxy, preferably C
1-6
alkoxy, or haloalkyl, preferably C
1-6
haloalkyl groups.
As a rule, aromatic or heteroaromatic groups are preferred, which are substituted by at least one electron-withdrawing group, in particular, by one or more halogen atoms, nitro, cyano or haloalkyl groups.
In general terms, unless otherwise stated herein, the term “alkyl” or “haloalkyl” as used herein with respect to a radical or moiety refers to a straight or branched chain radical or moiety. As a rule, such radicals have up to 10, in particular up to 6 carbon atoms. Typically, an alkyl or haloalkyl moiety has from 1 to 6 carbon atoms, preferably from 1 to 3 carbon atoms. A preferred alkyl moiety is the methyl, ethyl or isopropyl group.
If R
1
and R
2
together with the interjacent ring form a heterocyclic group, it is preferably a heterocyclic group having 5 to 8 ring atoms and preferably a piperidin-1-yl or a morpholin-1-yl group.
Preferred haloalkyl groups are poly- or perhalogenated alkyl groups of formula —(CX
2
)
n
—Y, in which n is an integer of 1 to 10, preferably, 1 to 6, in particular, 1 to 3, X represents fluorine or chlorine and Y is hydrogen or X. A preferred perhalognated alkyl moiety is a pentafluoroethyl, or especially a difluoro- or a trifluoromethyl group.
Optionally substituted moieties may be unsubstituted or have from one up to the maximal possible number of substituents. Typically, 0 to 2 substituents are present.
Further preferred embodiments of the process according to the present invention are a process wherein:
the concentrated sulfuric acid is added slowly to compound of formula II at temperatures between 1 about 110 and 150° C. (step a);
the mixture of the heteroaryltrichloromethane compound of formula II and 1.0 to 1.5 equivalents of concentrated sulfuric acid is kept at temperatures between about 110 and 150° C. (step a);
the intermediate product formed in step a) is added to the amine or alcohol of formula III in melted form (step b);
the heteroaryltrichloromethane compound is treated with concentrated sulfuric acid containing less than 3 wt % of water;
the intermediate product formed in step a) is treated with a straight-chained or branched aliphatic alcohol having 1 to 6 carbon atoms (step b), in particular with ethanol or isopropanol;
in the event that the intermediate of step a) has not been treated with an alcohol, the reaction of step b) is carried out in the presence of a tertiary amine as a base and an aromatic hydrocarbon as a diluent;
in the event that the intermediate of step a) has been treated with an alcohol (step b), the reaction with the amine of formula III is carried out in the presence of a metal alkoxide as a base and an aromatic hydrocarbon as a diluent;
the intermediate product formed in step a) comprises a compound of formula IV and/or V
or a structure isomeric form thereof; or preferably, said intermediate essentially consists of a compound of formula IVa1 and/or Va1
in the event that X represents NR
2
, R
1
represents preferably a phenyl group being substituted by one or two halogen atoms and/or haloalkyl groups and R
2
represents preferably a hydrogen atom.
Another aspect of the present invention is a process for the preparation of a (hetero)aryloxyhetero-arylcarboxylic amide or ester of formula VI from the heteroarylcarboxylic amide or ester of formula I or a salt thereof obtained according to the present invention.
Further preferred embodiments of the process for preparation of the compounds of formula VI according to the present invention are a
Brink Monika
Heinz Willi
Knell Marcus
Wevers Jan Hendrik
American Cyanamid Company
Davis Zinna Northington
Maurer Barbara V.
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