Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2000-04-12
2001-08-28
Ford, John M. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
active
06281358
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to an improved process for the preparation of substituted pyrimidines.
Pyrimidines, which are substituted in the 4-position by a hydrocarbyloxy or hydrocarbylthio group are of great commercial interest as highly effective pesticides or pharmaceuticals. U.S. Pat. No. 3,498,984 discloses 2-phenyl4-thiopyrimidines with interesting pharmaceutical properties. U.S. Pat. No. 5,824,624 describes herbicidal compositions comprising 2-phenyl-4-oxypyrimidines. The International Patent Applications WO 98/40379 and WO 98/56789 disclose herbicidal 4-oxypyrimidines, in which a 5-membered heteroaromatic group is attached to the 2-position of the pyrimidine moiety.
These compounds can be prepared for example in a multi-step process including the steps of treating a benzamidine hydrochloride with a substituted acetylacetate in the presence of a strong base to form a 2-phenylpyrimid-4-one, which is subsequently treated with a halogenating agent, in particular a phosphoryl halide to yield a 4-halo-2-phenylpyrimidine, which is reacted with an alcohol or a thioalcohol.
However, this process cannot be used for manufacture of relatively large quantities on an industrial scale due to the high risk of uncontrollable heat generation during the aqueous work up of the halogenation step.
W. Schroth et al., disclose the preparation of 1,3-thiazin-6-thiones by condensation of 3,3-dichloroacrolein and thioamides in the presence of trifluoroborane.
However, there is no motivation to apply this reaction on the manufacture of substituted pyrimidines, especially, since trifluoroborane is not applicable in large scale productions.
SUMMARY OF THE INVENTION
The present invention provides an effective and efficient process for the preparation of substituted pyrimidines of formula I,
wherein
R
1
and R
2
each independently represent an optionally substituted alkyl, cycloalkyl, phenyl or heteroaryl group,
R
3
and R
4
each independently represent a hydrogen atom or an optionally substituted alkyl or phenyl group, and X represents O or S, which comprises reacting an amidine of formula II,
or a salt thereof, wherein R
1
has the meaning given for formula I, with a 3,3-disubstituted vinylcarbonyl compound of formula III
wherein R
3
and R
4
have the meaning given, and L represent a halogen atom or a group of formula —X—R
2
,
(a) in an inert solvent, in the presence of a base and a compound of formula IV
H—X—R
2
(IV)
wherein X and R
2
have the meaning given, in the event that L represent a halogen atom, or
(b) in an inert solvent and in the presence of a base, in the event that L represents a group of formula —X—R
2
.
It is, therefore, an object of the present invention to provide an efficient new process for the preparation of substituted pyrimidines.
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 PREFERRED EMBODIMENTS
When any groups are designated as being optionally substituted, the substituent groups which are optionally present may be any of those customarily employed in the modification and/or development of pesticidal/pharmaceutical compounds and are especially substituents that maintain or enhance the herbicidal activity associated with the compounds of the present invention, or influence persistence of action, soil or plant penetration, or any other desirable property of such herbicidal compounds. There may be one or more of the same or different substituents present in each part of the molecules.
In relation to moieties defined above as comprising an optionally substituted alkyl or cycloalkyl group, specific examples of such substituents include phenyl, halogen atoms, nitro, cyano, hydroxyl, C
1-4
-alkoxy, C
1-4
-haloalkoxy and C
1-4
-alkoxycarbonyl groups.
In relation to moieties defined above as comprising an optionally substituted phenyl or heteroaryl group, optional substituents include halogen, especially fluorine, chlorine and bromine atoms, and nitro, cyano, amino, hydroxyl, C
1-4
-alkyl, C
1-4
-alkoxy, C-
1-4
-haloalkyl, C
1-4
-haloalkoxy, C
1-4
-haloalkylthio and halosulfanyl groups such as SF
5
, 1 to 5 substituents may suitably be employed, 1 to 2 substituents being preferred. Typically haloalkyl, haloalkoxy and haloalkylthio groups are trifluoromethyl, trifluoromethoxy, difluoromethoxy and trifluoromethylthio groups.
In general terms, unless otherwise stated herein, the term alkyl 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. Suitably an alkyl moiety has from 1 to 6 carbon atoms, preferably from 1 to 3 carbon atoms. A preferred alkyl moiety is the methyl or especially the ethyl group.
In general terms, unless otherwise stated herein, the term cycloalkyl as used herein with respect to a radical or moiety refers to a cycloalkyl radical which has up to 10, in particular up to 8 carbon atoms. Suitably a cycloalkyl moiety has from 3 to 6 carbon atoms, preferably from 3 or 6 carbon atoms. A preferred cycloalkyl moiety is the cyclopropyl, cyclopentyl and the cyclohexyl group.
In general terms, unless otherwise stated herein, the term heteroaryl as used herein with respect to a radical or moiety refers to a nitrogen containing 5- or 6-membered heteroaromatic radical or moiety. As a rule, such radicals exhibit at least one nitrogen atom and in the case of the five-membered radicals optionally one oxygen or sulfur atom; they are preferably selected from the 5-membered azoles, diazoles, triazoles, thiazoles, isothiazoles, thiadiazoles, in particular pyrrole and pyrazole and the 6-membered azines and diazines, in particular pyridine, pyrimidine, pyridazine and pyrazine.
In a preferred embodiment R
1
represents an optionally substituted phenyl, pyrid-3-yl, pyridazine-2-yl, pyrazine-3-yl, thiazol-2-yl, oxazol-2-yl, 1,3,4-thiadiazol-2-y, 1,2,4-oxadiazol-2-yl, 1,3,4oxadiazol-2-yl, pyrazol-1-yl or C
3-6
cycloalkyl group.
In a preferred embodiment R
2
represents an optionally substituted phenyl, pyrid-2-yl, pyrid-3-yl, pyrid4-yl, pyrazol-5-yl, pyridazine-2-yl or C
3-6
cycloalkyl group.
The groups R
1
and R
2
each independently are preferably substituted by one or more alkyl, fluoroalkyl, alkoxy or fluoroalkoxy group.
Suitable bases are weak organic or inorganic bases, preferably alkali hydrogencarbonates, such as sodium hydrogencarbonate, alkali carbonates, such as potassium carbonate or sodium carbonate, and tertiary amines, such as pyridine or triethylamine.
Further preferred embodiments of the process according to the present invention are a processes wherein:
the reaction is carried out in the presence of a base selected from the group consisting of, alkali carbonates and tertiary amines, in particular potassium carbonate or sodium carbonate;
the amidine of formula II to 3,3-disubstituted vinylcarbonyl compound of formula III molar ratio is from 1:5 to 1:0.5, in particular from 1:1.5 to 1:0.7, most preferred from 1:1.1 to 1:0.9;
the reaction step further comprises stirring a mixture consisting essentially of the amidine of formula II, the 3,3-disubstituted vinylcarbonyl compound of formula III, an inert diluent, a base and an optionally substituted alcohol, thioalcohol, phenol or thiophenol at a temperature from 0° C. to 150° C., preferably from 60° C. to 145° C., in particular from 80° C. to 140° C., most preferred at about the boiling point of the diluent;
the inert diluent is selected from the group consisting of acetonitrile, benzene, toluene, xylene, hexane, cyclohexane, dichloromethane, tetrachloromethane, diethylether, diisopropylether, tert-butylmethylether, 2,2-dimethoxypropane, dimethoxyethane, diethoxyethane, tetrahydrofuran, tetrahydropyran, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide and dioxane, and a mixture thereof, in particular toluene, dimethoxyethane or acetonitrile;
R
1
represents a phenyl group which is subs
Gutheil Dieter
Meyer Oliver
American Cyanamid Company
Costello C. F.
Ford John M.
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