Process for the production of 3-aryl-uracils

Details Process for the production of 3-aryl-uracils Process for the production of 3-aryl-uracils

1999-03-22

2001-03-27

Shah, Mukund J. (Department: 1611)

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

Organic compounds

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

34

Reexamination Certificate

active

06207830

ABSTRACT:

The present invention relates to a new process for the production of 3-phenyl-uracils, by reacting phenylisocyanates with N-alkyl-enamines.
From WO 95/17931, it is known that compounds of formulae A and B
wherein Z
1
and Z
2
denote oxygen or sulphur, whereby at least one of the groupings denotes sulphur; Ry denotes hydrogen or alkyl, alkenyl, alkinyl or alkylcarbonyl, Rs denotes hydrogen, halogen, cyano or optionally substituted alkyl, Rt denotes hydrogen or halogen, Rv denotes halogen, cyano, nitro, amino or an aminoalkylsulphonylalkyl group and Rz denotes alkyl or halogen-alkyl, may be produced in a manner whereby an enamine of formula C
wherein Rx denotes alkyl, is reacted with a cyanoaryliso(thio)cyanate of formula D
optionally in the presence of a reaction excipient and optionally in the presence of a diluent.
The reactions disclosed specifically in the preparation examples are carried out in a solvent mixture of dimethylformamide/toluene at temperatures of −70° C. or −15° C., whereby 1 equivalent of sodium hydride is respectively used as base. The yields of only 9 or 25% of theory attained in these reactions are however completely unsatisfactory especially for large scale usage.
It has now surprisingly been found that the yields of such reactions may be increased considerably if the reaction is carried out in a special solvent in the presence of a defined quantity of certain selected bases in a narrowly restricted temperature range especially adapted thereto.
In accordance with the invention, it is therefore proposed that compounds of formula I
wherein
R
1
signifies methyl or ethyl;
R
2
signifies —CF
3
, —CClF
2
, —CCl
2
F or —C
2
F
5
;
Q is a group
X and Y, independently of one another, are oxygen or sulphur;
R
3
signifies hydrogen, fluorine or chlorine;
R
4
signifies hydrogen, fluorine, chlorine, bromine, cyano, nitro, methyl or difluoromethyl;
R
5
signifies hydrogen, halogen, cyano, nitro, hydroxy, C
1-6
-alkoxy, C
1-6
-alkylthio, C
2-6
-alkenyloxy,
C
2-6
-alkinyloxy, C
1-6
-halogenalkoxy, C
2-6
halogen-alkenyloxy, C
2
-E
8
-alkylcarbonyl-alkoxy, C
2-8
-alkoxycarbonylalkoxy, C
1-3
-alkyl-oxiranylmethoxy,
C
4-8
-alkenyloxycarbonylalkoxy or C
4-8
-alkinyloxycarbonylaikoxy;
R
20
is hydrogen or C
1-4
-alkyl;
R
21
and R
22
, independently of one another, signify C
1-4
-alkyl; or R
21
and R
22
together signify a
C
2-3
-alkylene bridge;
R
23
signifies cyano or COR
6
;
R
24
signifies hydrogen or halogen;
R
6
signifies OH, C
1-6
-alkoxy, C
2-6
-alkenyloxy, C
2-6
-alkinyloxy, C
2-8
-alkoxyalkoxy, C
3-6
-cycloalkoxy, C
3-6
-cycloalkenyloxy, C
3-6
-cycloalkyl-C
1-6
-alkoxy, C
1-6
-halogen-alkoxy, C
2-6
-halogen-alkenyloxy, C
1-6
-hydroxycarbonylalkoxy, C
3-8
-alkoxycarbonylalkoxy, C
3-8
-alkenyloxycarbonylalkoxy, C
3-8
-alkinyloxycarbonylalkoxy, N(C
1
l
3
-alkyl)
2
or N(C
3-4
-alkenyl)
2
;
R
7
signifies C
1-6
-alkyl, C
2-6
-alkenyl, C
2-6
-alkinyl, C
2-8
-alkoxyalkyl, C
3-6
-cycloalkyl, C
1-6
-halogen-alkyl, C
2-6
-halogen-alkenyl, C
2-6
-alkylsulfonyloxyalkyl, C
1-10
-phenylsulfonyloxyalkyl, N(C
1-5
-alkyl)
2
or diallylamino;
R
8
signifies hydrogen, C
1-6
-alkyl, C
2-6
-alkenyl, C
2-6
-alkinyl, C
2
-C
10
-alkoxyalkyl, C
3-6
-cycloalkyl, C
3-6
-cycloalkenyl, C
1-6
-halogen-alkyl, C
3-6
-halogen-alkenyl, C
2-6
-hydroxycarbonylalkyl, C
3-8
-alkoxycarbonylalkyl, C
3-8
-alkenyloxycarbonylalkyl or C
3-8
-alkinyloxycarbonylalkyl;
R
9
signifies hydrogen, OH, CH
2
COOR
15
, CH
2
CON(C
1-4
-alkyl)
2
, CH
2
CON(C
3-4
-alkenyl)
2
, COOR
16
, CON(C
3-4
-alkyl)
2
, CON(C
3-4
-alkenyl)
2
, C
1-6
-alkyl, hydroxy-C
1-6
-alkyl, C
2-10
-alkoxycarbonyl-alkoxy or C
2-8
-alkoxyalkyl;
R
10
signifies hydrogen, Cyano, C
1-6
-alkyl, C
2-6
alkenyl, C
2-6
-alkinyl, hydroxy-C
1-6
-alkyl, C
2-8
-alkoxyalkyl, C
3-6
-cycloalkyl, C
1-6
-halogen-alkyl, COOR
17
, CON(C
1-4
-alkyl)
2
or CON(C
3-4
-alkenyl)
2
;
R
11
signifies hydrogen, C
1-6
-alkyl or C
1-6
-halogen-alkyl;
R
12
signifies hydrogen, C
1-6
-alkyl, C
1-6
-halogen-alkyl, CH
2
OH, C
2-6
-alkoxyalkyl, C
2-6
-halogenalkoxyalkyl, COOR,
8
, CON(C
14
-alkyl)
2
or CON(C
3-4
-alkenyl)
2
;
R
13
signifies hydrogen, C
3-16
-trialkylsilyloxy, C
1-6
-alkoxy, chlorine, C
1-6
-alkyl, C
2-6
-alkenyl, C
2-6
-alkinyl, C
3-6
-cycloalkyl, C
3-6
-cycloalkenyl, C
1-6
-halogen-alkyl, C
2-6
-halogen-alkenyl or C
1-6
-hydroxycarbonylalkyl;
R
14
signifies hydrogen, C
1-6
-alkyl or C
1-6
-halogenalkyl;
R
15
signifies hydrogen, C
1-6
-alkyl, C
2-6
-alkenyl, C
2-6
-alkinyl, C
2-8
-alkoxyalkyl, C
3-6
-cycloalkyl, C
3-8
-cycloalkenyl, C
1-6
-halogen-alkyl, C
2-6
-halogen-alkenyl, C
2-6
-hydroxycarbonylalkyl, C
3-8
-alkoxycarbonylalkyl, C
3-8
-alkenyloxycarbonylalkyl or C
3-8
-alkinyloxycarbonylalkyl;
R
16
signifies hydrogen, C
1-6
-alkyl, C
2-6
-alkenyl, C
2-6
-alkinyl, C
2-8
-alkoxyalkyl, C
3-6
-cycloalkyl, C
3-6
-cycloalkenyl, C
1-6
-halogen-alkyl, C
2-6
-halogen-alkenyl, C
2-6
-hydroxycarbonylalkyl, C
3-8
-alkoxycarbonylalkyl, C
3-8
-alkenyloxycarbonylalkyl or C
3-8
-alkinyloxycarbonylalkyl;
R
17
signifies hydrogen, C
1-6
-alkyl, C
2-6
-alkenyl, C
2-6
-alkinyl, C
2-8
-alkoxyalkyl, C
3-6
-cycloalkyl, C
3-6
-cycloalkenyl, C
1-6
-halogen-alkyl, C
2-6
-halogen-alkenyl, C
2
r-hydroxycarbonylalkyl, C
2-8
-alkoxycarbonylalkyl, C
3-8
-alkenyloxycarbonylalkyl or C
3-8
-alkinyloxycarbonylalkyl; and
R
18
signifies hydrogen, C
1-6
-alkyl, C
2-6
-alkenyl, C
2-6
-alkinyl, C
2-8
-alkoxyalkyl, C
3-6
-cycloalkyl, C
3-6
-cycloalkenyl, C
1-6
-halogen-alkyl, C
2-6
-halogen-alkenyl, C
2-6
-hydroxycarbonylalkyl, C
3-8
-alkoxycarbonylalkyl, C
3-8
-alkenyloxycarbonylalkyl or C
3-8
-alkinyloxycarbonylalkyl, are produced in a manner whereby a compound of formula II
O═C═N—Q  (II)
wherein Q has the significance given under formula I, is reacted at a temperature of −5° C. to +50° C. with an enamine of formula III
wherein R
1
and R
2
have the significances given under formula I, and R
19
signifies C
1
-C
6
-alkyl, in pure dimethylformamide, dimethyl sulphoxide, acetonitrile, propionitrile, ethyl acetate, tetra-hydrofuran, dioxane, N-methylpyrrolidone, methyl-tert.-butylether, dimethylacetamide or toluene or mixtures thereof as solvents, in the presence of 0.1 to 0.4 equivalents of a base selected from potassium tert.butylate, sodium tert.butylate, sodium methylate, sodium ethylate, potassium methylate, potassium ethylate, sodium hydride, potassium hydride, sodium pentylate, potassium pentylate and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), preferably potassium tert.butylate and potassium tert.pentylate with respect to the employed enamine of formula III.
The alkyl groups present in the definitions of substituents may be straight-chain or branched, and denote for example methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl or decyl, as well as the branched isomers thereof. Alkoxy, alkylthio, halogen-alkyl, alkylamino, alkenyl and alkinyl groups are derived from the said alkyl groups. The alkenyl and alkinyl groups may be unsaturated once or many times. For definitions such as C
3-8
-alkinylcarbonylalkyl, the carbonyl atom is not counted as a carbon atom.
Appropriate cycloalkyl substituents contain 3 to 6 carbon atoms and are e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Corresponding cycloalkenyl substituents may be unsaturated once or also many times, as for example cyclopentadienyl or cyclohexadienyl.
Halogen normally signifies fluorine, chlorine, bromine or iodine. The same also applies to halogen in conjunction with other significances, e.g. halogen-alkyl.
The preferred base in the process according to the invention is potassium tert.butylate. The base is preferably used in an amount of 0.1 to 0.4, preferably 0.15 to 0.3, especially 0.2 or 0.3 equivalents in relation to the employed enamine of formula III. Amounts of base of 0.25 to 0.35 and 0.2 to 0.4 equivalents are also suitable.
A preferred temperature range is 10° C. to 50° C., especially preferred 20° C. to 40° C. Further suitable temperature ranges are −5° C. to +40° C., especially 0° C. to +20° C., in particular 0° C.

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