Process for the preparation of 6-(perfluoroalkyl) uracil...

Details Process for the preparation of 6-(perfluoroalkyl) uracil... Process for the preparation of 6-(perfluoroalkyl) uracil...

2001-02-28

2001-11-06

Ford, John M. (Department: 1624)

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

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C544S310000

Reexamination Certificate

active

06313295

ABSTRACT:

BACKGROUND OF THE INVENTION
6-(Perfluoroalkyl)uracil compounds are useful as herbicidal agents and methods for their preparation are known in the art. 6-(Perfluoroalkyl)uracil compounds may be prepared by reacting 2-(N,N-disubstituted)amino-4-(per-fluoroalkyl)-1,3-oxazin-6-one compounds with amine compounds.
Bull. Soc. Chem. Belg., 101(4), pages 313-321 (1992) discloses that 2-(N,N-dialkyl)amino-4-(trifluoromethyl)-1,3-oxazin-6-one compounds are prepared by reacting ethyl 3-amino-4,4,4-trifluorocrotonate with phosgene iminium chloride compounds. However, this method is not entirely satisfactory because the required phosgene iminium chloride compounds are difficult to handle and relatively expensive. Accordingly, a need exists in the art for an improved process for the preparation of 6-(perfluoroalkyl)uracil compounds which avoids the use of 2-(N,N-disubstituted)amino-4-(perfluoroalkyl)-1,3-oxazin-6-one compounds.
It is, therefore, an object of the present invention to provide an improved process for the preparation of 6-(perfluoroalkyl)uracil compounds which avoids the use of 2-(N,N-disubstituted)amino-4-(perfluoroalkyl)-1,3-oxazin-6-one compounds.
Other objects and advantages of the present invention will be apparent to those skilled in the art from the description below and the appended claims.
SUMMARY OF THE INVENTION
The present invention provides a new process for the preparation of 6-(perfluoroalkyl)uracil compounds having the structural formula I
wherein
n is an integer of 1, 2, 3, 4, 5 or 6;
Y is hydrogen or C
1
-C
6
alkyl; and
Q is a C
1
-C
6
alkyl group or an optionally substituted phenyl, benzyl, heteroaryl or methyleneheteroaryl group,
which process comprises:
(a) reacting a carbamate compound having the structural formula II
 wherein
Z and Z
1
are each independently C
1
-C
6
alkyl or benzyl optionally substituted on the phenyl ring with any combination of from one to three halogen, C
1
-C
4
alkyl or C
1
-C
4
haloalkyl groups; and
n and Y are as described above, with an amine compound having the structural formula III
QNH
2
  (III)
wherein Q is as described above, in the presence of a base, to form the 6-(perfluoroalkyl)uracil compound of formula I wherein Y is hydrogen or C
1
-C
6
alkyl; and
(b) optionally alkylating the formula I compound wherein Y is hydrogen to form the formula I compound wherein Y is C
1
-C
6
alkyl.
DETAILED DESCRIPTION OF THE INVENTION
In a preferred embodiment of the present invention, a carbamate compound of formula II is reacted with an amine compound of formula III and a base, preferably at a temperature ranging from about 20° C. to 150° C., in the presence of a solvent.
In another preferred embodiment of the present invention, the double bond in the formula II compounds is predominately in the (Z)-configuration.
Advantageously, the present invention provides an improved process for the preparation of 6-(perfluoroalkyl)-uracil compounds which avoids the use of 2-(N,N-disubstituted)amino-4-(perfluoroalkyl)-1,3-oxazin-6-one compounds.
The product formula I compounds may be isolated using conventional isolation procedures such as diluting the reaction mixture with water and separating the product or extracting the product with a suitable extraction solvent. In the isolation procedure, conventional extraction solvents such as diethyl ether, ethyl acetate, toluene, methylene chloride, and the like, and mixtures thereof may be utilized.
Bases suitable for use in the process of the present invention include, but are not limited to, tri(C
1
-C
6
alkyl)amines such as trimethylamine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine and the like; heterocyclic tertiary amines such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane, pyridine, substituted pyridines, quinoline, substituted quinolines and the like; and alkali metal C
1
-C
6
alkoxides such as potassium tert-butoxide, sodium tert-butoxide and the like. Preferred bases include 1,8-diazabicyclo[5.4.0]undec-7-ene and 1,5-diazabicyclo[4.3.0]non-5-ene.
Solvents suitable for use in step (a) of the process of this invention include, but are not limited to, carboxylic acid amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; dialkyl sulfoxides such as dimethyl sulfoxide and the like; aromatic hydrocarbons such as toluene, benzene, xylenes, mesitylene and the like; halogenated aromatic hydrocarbons such as chlorobenzene, fluorobenzene and the like; aliphatic hydrocarbons such as pentane, hexane, heptane and the like; halogenated aliphatic hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; alcohols such as methanol, ethanol, n-propanol, sec-propanol and the like; ketones such as acetone, methyl ethyl ketone and the like; ethers such as diethyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane and the like; nitrites such as acetonitrile, propionitrile and the like; and water; and mixtures thereof.
Alkylation procedures suitable for use in this invention include conventional procedures known in the art. In a preferred embodiment of this invention, the step (b) alkylation procedure comprises reacting the formula I compound wherein Y is hydrogen with an alkyl halide having the structural formula IV or a dialkylsulfate ester having the structural formula V
wherein X is chlorine, bromine or iodine, and Y is C
1
-C
6
alkyl in the presence of a base.
Bases suitable for use in the alkylation procedures of this invention include conventional bases known in the art including, but not limited to, alkali metal hydrides such as sodium hydride and the like; alkali metal C
1
-C
6
alkoxides such as potassium tert-butoxide, sodium tert-butoxide and the like; alkali metal hydroxides such as potassium hydroxide, sodium hydroxide and the like; alkali metal carbonates such as sodium carbonate, potassium carbonate and the like; alkaline earth metal hydroxides such as calcium hydroxide and the like; and alkaline earth metal carbonates such as calcium carbonate and the like.
Preferred-formula II compounds for use in the process of this invention are those wherein
Y is hydrogen or C
1
-C
4
alkyl;
Z and Z
1
are each independently C
1
-C
4
alkyl; and
n is 1.
More preferred carbamate compounds of formula II for use in the process of the present invention are those wherein
Y is hydrogen or methyl;
Z and Z
1
are each independently methyl or ethyl; and
n is 1.
Preferred formula I compounds which may be prepared by the process of the present invention are those wherein
n is 1;
Y is hydrogen or C
1
-C
4
alkyl;
Q is
 G is CH
2
or a bond;
G
1
is CX
5
or N;
G
2
is CX
4
or N;
X
1
is hydrogen, halogen or a C
1
-C
6
alkyl group optionally substituted with one epoxy group,
X
2
is hydrogen, halogen NRR
1
, CO
2
R
2
, C(O)R
3
, OR
4
, SO
2
R
5
, SO
2
NR
6
R
7
, C(R
8
) (OR
9
)
2
, C(R
10
)═NOR
11
, C(R
12
)═C (R
95
)—C(OR
14
)═NOR
15
, CH
2
O—NCO
2
R
16
, CH(O—C
1
-C
3
alkyl)
2
,
C
2
-C
6
alkenyl optionally substituted with P(O)(O—C
1
-C
3
alkyl)
3
,
1,3-dioxolane optionally substituted with one C
1
-C
6
alkoxy group or one or two C
1
-C
4
alkyl groups,
1,3-dioxolinone optionally substituted with one C
1
-C
6
alkoxy group or one or two C
1
-C
4
alkyl groups, or
C
1
-C
4
alkyl optionally substituted with halogen, diazole, triazole, S-alkyl or C
1
-C
4
alkyl, or with one CO
2
R
2
group and one halogen atom, or with one halogen and P(O)(OC
1
-C
3
alkyl)
2
, and
X
3
is hydrogen, halogen, C
1
-C
4
haloalkyl, CO
2
R
17
, cyano, C
1
-C
4
haloalkoxy, OR
18
or C
1
-C
4
alkyl, or
when X
1
and X
2
are taken together with the atoms to which they are attached, they may form a five- or six-membered ring wherein X
1
X
2
or X
2
X
1
is represented by:
—OC(R
20
)(R
21
)O—, —CH
2
S(O)
p
N(R
22
)—, —SC(R
23
)═N—, —CH═CH—CH(R
11
)O—, —OC(O)N—, —OC(R
24
)═N—, —ON(R
25
) C(O)—,
—OC(CO
2
R
26
)═C(R
27
)—, —NC (R
28
)═C(SR
29
)—, —CH═C(CO
2
R
30
)O—,
—CH
2
CH(R
31
)O—

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