Abstrict A compound represented by the formula (I) or its salt and herbicidal
and desiccant use thereof: ##STR1## wherein X, Y are independently
hydrogen, halogen, cyano, nitro, or (C.sub.1-6)haloalkyl; Z is oxygen
or sulfur; and Q is ##STR2##
Claims What is claimed is:
1. A compound represented by the formula (I) or its salts: ##STR41##
wherein X and Y are independently hydrogen, halogen, cyano, nitro,
or (C.sub.1-6)haloalkyl;
4. A herbicidal composition which comprises an effective amount
of a compound of claim 1 and an agricultural adjuvant.
5. A method for controlling weeds, which comprises applying to
the locus to be protected a herbicidally effective amount of a compound
of claim 1.
6. A method for controlling weeds in a corn field which comprises
applying a herbicidally effective amount of a compound of claim
1 to the corn field.
7. A method for controlling weeds in a soybean field which comprises
applying a herbicidally effective amount of a compound of claim
1 to the soybean field.
8. A method for controlling weeds, which comprises applying to
the locus to be protected a herbicidally effective amount of a compound
of claim 1 in combination with another herbicide for providing an
additive or synergistic herbicidal effect.
9. A method for controlling weeds of claim 5 wherein the compound
of claim 1 is applied to soil as a preemergent herbicide.
10. A method for controlling weeds of claim 5 wherein the compound
of claim 1 is applied to plant foliage.
11. A method for controlling weeds of claim 8 wherein the another
herbicide is an acetanilide or sulfonylurea.
12. A method to desiccate a plant of which comprises applying to
the plant a compound of claim 1.
13. A method to desiccate a plant of claim 12 wherein the plant
to which the compound is applied is a potato plant or a cotton plant.
Description A class of diaryl ethers and compositions thereof which are useful
in the control of weeds is of the general formula ##STR3## wherein
X, Y are hydrogen, halogen, cyano, nitro, or (C.sub.1-6)haloalkyl;
Z is oxygen or sulfur;
Q is selected from ##STR4##
Ar is a substituted or unsubstituted aryl or heteroaryl ring; When
Q is Q.sub.3 or Q.sub.6 substituted phenyl is excluded.
BACKGROUND OF THE INVENTION
Various substituted phenyl ethers (I.sup.1) are known in the literature.
##STR5##
Q may be pyrazole, imidazole, imidazolidine-24-dione, triazolinone,
tetrazolinone, aminouracil, etc. R may be hydrogen, alkyl, cycloalkyl,
alkenyl or alkynyl. U.S. Pat. No. 5496956 discloses arylpyrazoles
with the R group selected from propargyl, allyl, or substituted
alkyl. JP 6256312 discloses phenylimidazoles with the R group
selected from hydrogen, (C.sub.1-10)alkyl, (C.sub.1-5)haloalkyl,
(C.sub.3-5)alkenyl, (C.sub.3-6)cycloalkyl. U.S. Pat. No. 5125958
discloses triazolinones with the R group selected from substituted
phenyl group. JP 57197268 discloses hydantoins with the R group
selected lower alkyl. U.S. Pat. No. 4902337 discloses hydantoins
with the R group selected from hydrogen, alkyl, cycloalkyl, alkenyl
or alkynyl. JP 525173 discloses pyrimidinediones with the R group
selected from hydrogen, (C.sub.1-10)alkyl, (C.sub.1-5)haloalkyl,
(C.sub.3-5)alkenyl, (C.sub.3-5)alkynyl, or (C.sub.3-6)cycloalkyl.
U.S. Pat. No. 4985065 discloses phenyltetrazolinones with the
R group selected from substituted phenyl group. No heteroaryl derivatives
were claimed as R. WO 9602523 discloses substituted aryliminothiadiazoles
with the R group selected from hydrogen, alkyl, cycloalkyl, alkenyl
or alkynyl. U.S. Pat. No. 4452981 discloses phenylurazoles with
the R group selected from (C.sub.1-3)alkyl, allyl, or propargyl.
EP-A-517181 (which corresponds to U.S. Pat. No. 5280010) discloses
aminouracil compounds wherein Q is amino uracil and R is a lower
alkyl group. WO96/07323 and WO96/08151 disclose some known uracil
compounds. In WO96/08151 the generic representation is significantly
broader than the disclosures set forth in it, and in the prior art
patents. The specific aminouracil compounds of the formula (I) mentioned
below are not known and are novel.
The present invention reveals that some diaryl ethers represented
by the general formula (I) or their salts have a potent herbicidal
activity with good crop safety.
DESCRIPTION
The need continues for novel and improved herbicidal compounds
and compositions. This invention relates to novel diaryl ethers,
compositions comprising diaryl ethers, and the use of diaryl ethers
and compositions thereof as broad spectrum herbicides which are
effective against both monocot and dicot weed species in preemergence
and postemergence application and are sometimes safe to crops. The
compounds and compositions of the present invention can also be
sometimes used as desiccants. This invention also includes methods
of preparing these compounds and intermediates thereof as well as
methods of using the compound as herbicides.
This invention relates to diaryl ether compounds having the general
formula I and their salts ##STR6## wherein X, Y are independently
hydrogen, halogen, cyano, nitro, or (C.sub.1-6)haloalkyl and
Z is oxygen or sulfur and
Q is selected from ##STR7## R.sub.1 is halogen; R.sub.2 R.sub.3
R.sub.4 and R.sub.5 are independently hydrogen, (C.sub.1-6)alkyl,
or (C.sub.1-6)haloalkyl;
When R.sub.3 and R.sub.5 are taken together with the atoms to which
they are attached, they represent a four to seven membered substituted
or unsubstituted ring optionally interrupted by O, S(O).sub.n or
N--R.sub.4 and optionally substituted with one to three (C.sub.1-6)alkyl
group or one or more halogen atoms;
R.sub.6 is hydrogen, (C.sub.1-6)alkyl, (C.sub.2-6)alkenyl, (C.sub.2-6)alkynyl,
(C.sub.1-6)haloalkyl, (C.sub.2-6)haloalkepyl, (C.sub.2-6)haloalkynyl,
(C.sub.1-6)cyanoalkyl, (C.sub.1-6)alkoxy-(C.sub.1-6)alkyl, or (C.sub.1-6)alkylthio-(C.sub.1-6)alkyl;
A.sub.1 and A.sub.2 are independently oxygen or sulfur;
B is CH or N;
R.sub.7 and R.sub.8 are each independently hydrogen, (C.sub.1-6)alkyl
optionally substituted with one or more halogen atoms, or (C.sub.3
-C.sub.6)cycloalkyl optionally substituted with one or more halogen
atoms, and when R.sub.7 and R.sub.8 are taken together with the
atoms to which they are attached, they represent a four to seven
membered substituted or unsubstituted ring optionally interrupted
by O, S(O).sub.n or N--R.sub.4 and optionally substituted with
one to three (C.sub.1-6)alkyl groups or one or more halogen atoms;
n is an integer of 0 1 or 2.
R.sub.9 and R.sub.10 is hydrogen, (C.sub.1-6)alkyl, acyl, or (C.sub.1-6)alkylsulfonyl
or R.sub.9 and R.sub.10 may form a ring consisting of polymethylene,
(CH.sub.2).sub.m, groups, where m is an integer of 2 3 4 or 5
together with the nitrogen atom of NR.sub.9 R.sub.10 which may
or may not have a (C.sub.1-6)alkyl substituent.
D is carbon, oxygen, sulfur or a nitrogen atom, sulfoxide or sulfone;
n.sub.1 is 0 1 2 or 3;
R.sub.11 is hydrogen, hydroxyl, C.sub.1-3 alkoxy, C.sub.1-3 haloalkoxy,
C.sub.2-5 alkylcarbonyloxy, or C.sub.2-5 haloalkylcarbonyloxy, nitro,
or amino;
R.sub.12 is hydrogen, hydroxyl, or halogen;
When R.sub.11 and R.sub.12 are bonded to the same carbon atom,
they may form a carbonyl bond.
When R.sub.11 and R.sub.12 are bonded to adjacent carbon atoms,
they may form a epoxide ring;
The ring to which R.sub.11 and R.sub.12 are attached may be saturated
or unsaturated and may contain single or double bonds.
E-G is N.dbd.N, CH.dbd.N, N.dbd.CH, or CH.dbd.CH.
Some compounds of formula (1) and their intermediates may occasionally
exist as geometrical or optical isomers and the present invention
includes all of these isomeric forms
Some compounds of the formula (I) and their intermediates may form
a salt with an acidic substance or a basic substance. The salt with
an acidic substance may be an inorganic acid salt such as a hydrochloride,
a hydrobromide, a phosphate, a sulfate or a nitrate. The salt with
a basic substance may be a salt of an inorganic or organic base
such as a sodium salt, a potassium salt, a calcium salt, a quarternary
ammonium salt such as ammonium salt or a dimethylamine salt.
Ar is a substituted or unsubstituted aryl or heteroaryl ring; When
Q is Q.sub.3 or Q.sub.6 substituted or unsubstituted phenyl is
excluded.
This invention also relates to compositions containing those compounds
and methods for using those compounds and compositions. The compounds
and compositions of the present invention are especially useful
for the selective control of undesirable plant species occasionally
in the presence of crops. The compounds and compositions of the
present invention can also be used as desiccants.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a method for controlling undesirable
plant species by preemergence or postemergence application.
The diaryl ether compounds of this invention have the general formula
I ##STR8## wherein X, Y, Z, Ar, and Q are as described above.
The aryl in the definition of Ar may be phenyl or naphthyl, and
the heteroaryl in the definition of Ar may be a five or six membered
ring having at least one heterogeneous atom of nitrogen, oxygen
or sulfur, and for example may be pyridyl, pyrimidyl, pyridazinyl,
triazolyl, thiazolyl or isothiazolyl. The substituents for the substituted
aryl or heteroaryl ring may, for example, be halogen, (C.sub.1-6)alkyl,
halo(C.sub.1-6)alkyl, (C.sub.1-6)alkoxy, halo(C.sub.1-6)alkoxy,
(C.sub.1-6)alkylthio, (C.sub.1-6)alkylsulfonyl, (C.sub.1-6)alkylsulfinyl,
(C.sub.1-6)dialkylaminocarbonyl, cyano, nitro, amino, hydroxy, (C.sub.1-6)alkylsulfonylamino,
(C.sub.1-6)alkoxycarbonyl(C.sub.1-6)alkoxy, (C.sub.1-6)alkylcarbonylamino,
bisbenzoylamino, aminoacetyl, aminotifluoroacetyl, or amino(C.sub.1-6)allylsulfonate.
The number of substituents is one or more, for example up to five.
When the number is two or more, the substituents may be same or
different.
The alkyl group and alkyl part in the definition related to X,
Y, R.sub.2 to R.sub.12 and the substituents for the substituted
aryl and heteroaryl ring as Ar have the straighted or branched chains
with C.sub.1-6 preferably C.sub.1-4 such as methyl, ethyl, propyl,
butyl, pentyl, or hexyl. The alkenyl or alkynyl group and their
parts in the definition for R.sub.6 have also the straighted or
branched chains with C.sub.2-6 preferably C.sub.2-4 such as vinyl,
propenyl, butenyl, pentenyl, hexenyl, ethynyl, propynyl, butynyl,
pentynyl, or hexynyl.
The halogen atom and halogeno part in the definition related to
X, Y, R.sub.1 to R.sub.8 R.sub.11 and R.sub.12 are fluorine, chlorine,
bromine, or iodine. The haloalkyl, haloalkenyl or haloalkynyl group
constitutes the alkyl, alkenyl or alkynyl group and one or more
halogen atoms as mentioned above. When the number of halogen atom
is two or more, halogen atoms may be same or different.
Preferred formula I compounds of this invention are those wherein
X, Y are independently hydrogen, or halogen;
Z is oxygen or sulfur;
Q is selected from Q.sub.1 Q.sub.2 Q.sub.4 Q.sub.6 Q.sub.7
Q.sub.8 Q.sub.9 Q.sub.10 Q.sub.11 Q.sub.12 Q.sub.13 Q.sub.14
or Q.sub.15.
Ar is pyridyl, pyrimidyl, triazolyl, thiazolyl, isothiazolyl, or
phenyl or pyridyl, pyrimidyl, triazolyl, thiazolyl, isothiazolyl,
or phenyl substituted with up to five substituents independently
selected from bromo, chloro, fluoro, iodo, (C.sub.1 -C.sub.4)alkyl,
halo(C.sub.1-4)alkyl, (C.sub.1-4)alkoxy, (C.sub.1-4)alkylthio, halo(C.sub.1-4)alkoxy,
(C.sub.1-4)alkylsulfonyl, (C.sub.1
-C.sub.3)alkylsulfinyl, di(C.sub.1-4)alkylaminocarbonyl, cyano,
nitro, amino, hydroxy, (C.sub.1-4) alkylsulfonylamino, (C.sub.1-4)alkoxycarbonyl(C.sub.1-4)alkoxy,
or (C.sub.1-4)alkoxycarbonylamino; When Q is Q.sub.6 substituted
phenyl is excluded.
The most preferred formula I compounds of this invention are those
wherein
X is fluorine;
Y is chlorine;
Z is oxygen or sulfur;
Q is selected from Q.sub.1 Q.sub.2 Q.sub.4 Q.sub.6 Q.sub.7
Q.sub.8 Q.sub.9 Q.sub.10 Q.sub.11 Q.sub.12 Q.sub.13 Q.sub.14
or Q.sub.15.
Ar is 2-pyridyl, 3-pyridyl , 4-pyridyl , 3-bromo-2-pyridyl, 5-bromo-2-pyridyl,
6-bromo-2-pyridyl, 3-chloro-2-pyridyl, 5-chloro-2-pyridyl, 6-chloro-2-pyridyl,
3-fluoro-2-pyridyl, 5-fluoro-2-pyridyl, 6-fluoro-2-pyridyl, 3-cyano-2-pyridyl,
5-cyano-2-pyridyl, 6-cyano-2-pyridyl, 3-nitro-2-pyridyl, 5-nitro-2-pyridyl,
6-nitro-2-pyridyl, 3-trifluoromethyl-2-pyridyl, 4-trifluoromethyl-2-pyridyl,
5-trifluoromethyl-2-pyridyl, 6-trifluoromethyl-2-pyridyl, 5-amino-2-pyridyl,
3-dimethylaminocarbonyl-2-pyridyl, 3-methylsulfonyl-2-pyridyl, 3-isopropylsulfonyl-2-pyridyl,
6-chloro-3-trifluoromethyl-2-pyridyl, 356-trifluoropyridyl, 2-pyrimidyl,
4-pyrimidyl, 5-bromo-2-pyrimidyl, 4-chloro-2-pyrimidyl, 4-trifluoromethyl-2-pyrimidyl,
46-dimethoxy-2-pyrimidyl, 26-dimethoxy-4-pyrimidyl, 46-dimethoxy-2-triazinyl,
phenyl, 2-iodophenyl, 2-trifluoromethoxyphenyl, 2-nitrophenyl, 4-nitrophenyl,
4-aminophenyl, 4-hydroxyphenyl, 4-methylsulfonylaminophenyl, 4-(1-ethoxycarbonylethoxy)phenyl,
2-cyanophenyl, 2-cyano-3-fluorophenyl, 2-cyano-4-fluorophenyl, 2-amino-4-(1-ethoxycarbonylethoxy)-phenyl,
2-cyano-4-nitrophenyl, 4-amino-2-cyanophenyl, 4-nitro-2-trifluoromethylphenyl,
4-amino-2-trifluoromethylphenyl, 4-acetylamino-2-trifluoromethylphenyl,
4-(1-ethoxycarbonylethoxy)-2-nitrophenyl, 5-chloro-4-(1-ethoxycarbonylethoxy)-2-nitrophenyl,
3-methyl-4-nitro-5-isothiazolyl, or 5-nitro-2-thiazolyl; When Q
is Q.sub.3 Q.sub.6 or Q.sub.14 substituted or unsubstituted phenyl
is excluded.
The intermediates II and III can be prepared by the methods mentioned
in Process (1). ##STR9##
Process (1) is carried out in two stages. The first step is the
reaction of an aminophenol with an aryl halide or an heteroaryl
halide with or without solvents. The solvents may include acetonitrile,
tetrahydrofuran, dimethyl imidazolidine, dimethylsulfoxide, hexamethylphosphoric
triamide, N,N-dimethylformamide, acetone, butan-2-one, benzene,
toluene or xylene, in the presence of a base such as potassium carbonate,
sodium carbonate, potassium hydroxide, sodium hydroxide, potassium
t-butoxide, potassium fluoride, or sodium hydride. Catalysts may
or may not be used. Such catalysts include copper(1)chloride, copper(1)oxide,
copper, copper(1)alkoxide, alkyl cuprate, palladium(0), tetrabutylammonium
halides, or 8-quinolinol. The reaction temperature is usually from
0.degree. C. to 250.degree. C., preferably from 20.degree. C. to
120.degree. C. The reaction time is from 1 to 12 hours, preferably
from 2 to 6 hours. The diaryl ethers (II) may also be prepared by
treatment of an aminophenol with aryl-lead tricarboxylates, triphenylbismuth-diacetate,
triphenylbismuth-trifluoroacetate or diphenyliodonium halides in
the presence of solvents such as benzene, toluene, dichloromethane,
dichloroethane, chloroform or water, with or without catalysts such
as copper, or a transition metal. The temperature is usually from
0.degree. C. to the reflux temperature of the mixture, and the reaction
time from 10 minutes to 72 hours. The temperature is preferably
from 20.degree. C. to the reflux temperature of the mixture, and
the time preferably 2 to 6 hours.
The second step requires treatment of the amine (II) with phosgene
or triphosgene in a solvent such as hexane, heptane, benzene, toluene,
xylene, or ethyl acetate. The reaction temperature is usually from
0.degree. C. to the reflux temperature of the mixture, preferably
at the reflux temperature of the mixture. The reaction time is usually
from 30 minutes to 6 hours, preferably from 2 to 3 hours. ##STR10##
In Process (2) the ether linkage is formed using the conditions
described in the first stage of Process (1). ##STR11##
In Process (3) the ether linkage is formed using the conditions
described in the first stage of Process (1). ##STR12##
Process (4) proceeds in three stages. The first step is the formation
of a diazonium salt of aniline (II) usually in an acidic medium
such as conc. hydrochloric acid when treated with aqueous sodium
nitrite solution. It is reduced in the presence of a reducing agent
to give the corresponding hydrazine derivative. Such a reducing
agent could be an inorganic compound such as hydrated tin(II)chloride.
This is treated with a ketoacid such as pyruvic acid in aqueous
solution. The reaction temperature is between -15.degree. C. to
30.degree. C. and the time from 30 minutes to 4 hours. The preferred
temperature initially is between 0.degree. C. and 5.degree. C. and
later at 20.degree. C. to 30.degree. C. and the preferred time is
from 30 to 60 minutes.
In the second step the prepared hydrazone (VIII) is treated with
diphenylphosphoryl azide in an inert solvent such as benzene, toluene,
xylene, hexane, in the presence of a base such as triethylamine
or pyridine. The reaction temperature is between 20.degree. C. and
the reflux temperature of the mixture and the time from 30 minutes
to 6 hours. Preferably the temperature is the reflux temperature
of the mixture and the time is from 1 to 2 hours.
The final stage is the alkylation of (IX) in an inert solvent such
as diethyl ether, dioxane or tetrahydrofuran with an alkylating
agent such as an alkyl halide, haloalkyl halide, or alkyl sulfate,
in the presence of a base such as sodium or potassium hydroxide,
sodium or potassium carbonate, pyridine or triethylamine with or
without a catalytic amount of a tetraalkylammonium salt. The reaction
temperature is between -40.degree. C. to 50.degree. C. and the time
from 30 minutes to 4 days. The preferred reaction temperature is
between 20.degree. C. to 30.degree. C., the preferred reaction time
is 2 days. ##STR13##
Process (5) proceeds in three stages. The first step is the treatment
of the isocyanate (IIIa) with ammonia in an inert solvent such as
hexane, benzene, toluene, xylene, diethyl ether, tetrahydrofuran
or dioxane. The reaction temperature is between -10.degree. C. to
100.degree. C. and the time from 15 minutes to 6 hours. The reaction
temperature is preferably between 0.degree. C. and 10.degree. C.,
and the time from 30 to 60 minutes.
The second step is the treatment of the urea (XI) with an acid
catalyst such as p-toluenesulfonic acid or amberlyst resin, and
a ketoester, in an inert solvent such as benzene, toluene, xylene,
hexane, at a temperature between 20.degree. C. and the reflux temperature
of the mixture, from 10 to 24 hours, to give the imidazolidinone
(XII). The temperature is preferably the reflux temperature of the
mixture and the time 12 to 16 hours.
The final stage is the alkylation of (XII) in an inert solvent
such as diethyl ether, dioxane, tetrahydrofuran, benzene, toluene,
xylene or hexane, with an alkylating agent such as an alkyl halide
or haloalkyl halide, in the presence of a base such as sodium or
potassium hydroxide, sodium or potassium carbonate, pyridine or
triethylamine. The reaction temperature is between 20.degree. C.
to the reflux temperature of the mixture, and the time from 30 minutes
to 20 hours. Preferably the temperature is between 50.degree. C.
and 100.degree. C. and the time from 12 to 16 hours. ##STR14##
Process (6) proceeds in three stages. The first step is the treatment
of the isocyanate (IIIb) with 22-dimethyl-5-(2-tetrahydropyrrolylidene)-13-dioxane-46-dione
in the presence of a base such as sodium methoxide, sodium ethoxide,
potassium t-butoxide, or sodium hydride in a solvent such as toluene,
N,N-dimethylformamide or dimethylsulfoxide. The reaction temperature
is between -40.degree. C. to the reflux temperature of the mixture
and the time from 30 minutes to 14 hours. Preferably the initial
temperature of the addition is between -30.degree. C. to -20.degree.
C., and further reaction requires temperatures of between 100.degree.
C. and 120.degree. C. The preferred time is from 4 to 5 hours.
The second step is the hydrolysis of the ether linkage under acidic
conditions in an inert solvent such as chloroform or methylene chloride,
using conc. sulfuric acid. The reaction temperature is between -20.degree.
C. to 50.degree. C. and the time from 30 minutes to 6 hours. Preferably
the addition is done at between 0.degree. C. to 5.degree. C., and
further reaction requires temperatures of between 20.degree. C.
and 30.degree. C. The preferred time is from 1 to 2 hours.
In the final step the ether linkage is formed using the conditions
described in the first stage of Process (1). ##STR15##
Process (7) proceeds in two stages. The first step is the formation
of the tetrazole ring (XVIII) by treatment of the isocyanate (III)
with trimethylsilyl azide with or without solvent. The reaction
temperature is between 100.degree. C. to the reflux temperature
of the mixture and the time from 1 to 48 hours. Preferably the temperature
is the reflux temperature of the mixture and the time 24 hours.
The final stage is the alkylation of (XVIII) in an inert solvent
such as acetone, diethyl ether, dioxane, tetrahydrofuran, benzene,
toluene, xylene, hexane, N,N-dimethyl-formamide or dimethylsulfoxide,
with an alkylating agent such as an alkyl halide or an haloalkyl
halide in the presence of a base such as sodium or potassium hydroxide,
sodium or potassium carbonate, pyridine or triethylamine. The reaction
temperature is between 50.degree. C. to 150.degree. C. and the time
from 30 minutes to 2 days. The preferred temperature range is between
70.degree. C. and 90.degree. C. and the time from 20 to 30 hours.
##STR16##
Process (8) proceeds in five stages. The first step requires treatment
of the amine (II) with thiophosgene in a solvent such as hexane,
heptane, benzene, toluene, xylene, or ethyl acetate. The reaction
temperature is usually from 0.degree. C. to the reflux temperature
of the mixture, preferably the addition is done at 0.degree. C.
to 5.degree. C., and further reaction requires temperatures heating
to the reflux temperature of the mixture. The reaction time is usually
from 30 minutes to 6 hours, preferably from 2 to 3 hours.
In the second step the isothiocyanate (XX) was treated with formic
hydrazide in an inert solvent such as toluene, tetrahydrofuran,
dioxane or diethyl ether. The reaction temperature is usually from
0.degree. C. to the reflux temperature of the mixture, preferably
at ambient temperature. The reaction time is usually from 30 minutes
to 10 hours, preferably from 3 to 4 hours.
The formyl hydrazines (XXI) were treated with phosgene or triphosgene
in a solvent such as hexane, heptane, benzene, toluene, xylene,
acetone, or ethyl acetate. The reaction temperature is usually from
-20.degree. C. to 50.degree. C., preferably between 0.degree. C.
and 25.degree. C. The reaction time is usually from 30 minutes to
6 hours, preferably from 1 to 2 hours.
The hydrolysis of the 3-formylthiadiazolidinones (XXII) is done
under acidic conditions in such solvents as acetone, butan-2-one,
methanol, ethanol, tetrahydrofuran, or N,N-dimethylformamide. The
acids may be sulfuric, hydrochloric or acetic acids and may be diluted.
The reaction temperature is usually from -20.degree. C. to 50.degree.
C., preferably between 0.degree. C. and 25.degree. C. The reaction
time is usually from 15 minutes to 6 hours, preferably from 30 minutes
to 2 hours.
The final stage is the alkylation of (XXIII) in an inert solvent
such as acetone, diethyl ether, dioxane, tetrahydrofuran, benzene,
toluene, xylene, hexane, N,N-dimethyl-formamide or dimethylsulfoxide,
with an alkylating agent such as an alkyl halide or a haloalkyl
halide, in the presence of a base such as sodium or potassium hydroxide,
sodium or potassium carbonate, pyridine or triethylamine. The reaction
temperature is between 30.degree. C. to the reflux temperature of
the mixture and the time from 30 minutes to 6 hours. The preferred
temperature range is between 50.degree. C. and 90.degree. C. and
the time from 1 to 3 hours. ##STR17##
In Process (9) amines (II) are transformed into the 24-imidazolidinediones
(XXVII) in three stages. In the first step treatment with a haloacetyl
halide, such as chloroacetyl chloride and an organic base such as
triethylamine or pyridine, in an inert solvent such as benzene,
toluene, xylene, tetrahydrofuran, or N,N-dimethylformamide gave
the chloroamides (XXV). The preferred acylating agent is chloroacetyl
chloride and the preferred base triethylamine. The preferred solvent
is toluene. The reaction may be carried out at temperatures between
-20.degree. C. and 150.degree. C., preferably between 25.degree.
C. and 50.degree. C. The reaction time may be from 30 minutes to
ten hours, preferably between 2 and 4 hours.
In the second step reaction of these chloroamides (XXV) with suitable
amines in a solvent such as C.sub.1-5 alcohols, tetrahydrofuran,
or dioxane gave amino-amides (XXVI). The preferred solvent is ethanol,
and the reaction may be carried out at temperatures between -20.degree.
C. and 150.degree. C., preferably between 25.degree. C. and 70.degree.
C. The reaction time may be from 30 minutes to ten hours, preferably
between 2 and 3 hours.
In the third step the amino-amides (XXVI) are treated with 11.sup.1
-carbonyldi-imidazole in an inert solvent such as benzene, toluene,
xylene, tetrahydrofuran, or N,N-dimethylformamide and yielded the
24-imidazlidinediones(XXVII). The preferred solvent is toluene,
and the reaction may be carried out at temperatures between -20.degree.
C. and 150.degree. C., preferably between 100.degree. C. and 120.degree.
C. The reaction time may be from 30 minutes to ten hours, preferably
between 2 and 3 hours. ##STR18##
Process (10) proceeds in three stages. The first is the reaction
of isothiocyanates (XXa) with a saturated cyclic heterocycle (XXVIII)
such as 1-ethyloxycarbonylhexahydropyridazine, where B.dbd.N and
f=2 and may or may not be done in two parts, (1) and (2). In part
(1) they are stirred together in an inert solvent such as benzene,
toluene, xylene, dioxane, hexane, ethyl acetate, tetrahydrofuran,
diethyl ether, or acetone. The reaction temperature is usually from
-70.degree. C. to the reflux temperature of the mixture, depending
on the nature of B, f, and R.sub.4. The reaction time is usually
from 30 minutes to 20 hours, depending on the nature of B, f, and
R.sub.4. In part (2) after removal of the solvent toluene, xylene,
or dioxane may be added, and also a weakly basic compound such as
sodium acetate. The reaction proceeds at a temperature of between
50.degree. C. to the reflux temperature of the mixture and the time
from 6 hours to 3 days. The preferred temperature is the reflux
temperature of the mixture and the time from 20 to 30 hours.
The second step is the hydrolysis of the ether linkage under acidic
conditions in an inert solvent such as chloroform or methylene chloride,
using conc. sulfuric acid. The reaction temperature is between -20.degree.
C. to 50.degree. C. and the time from 30 minutes to 6 hours. Preferably
at 0.degree. C. and a time of 1 to 2 hours.
The final step is the formation of the ether linkage to give (XXXI).
This is done using the conditions described in the first stage of
Process (1). ##STR19##
Process (11) is a one step process where a compound (XXb), which
may be an isocyanate or an isothiocyanate, reacts with a saturated
cyclic heterocycle (XXVIII), with or without solvents, to give the
product (XXXI). The reaction is enhanced by the presence of solvents
such as hexane, pentane, benzene, toluene, xylene, diethyl ether,
tetrahydro-furan, dioxane, acetone, butan-2-one, ethyl acetate,
N,N-dimethylformamide or dimethyl-sulfoxide, and is conducted between
-70.degree. C. to the reflux temperature of the mixture and from
15 minutes to 20 hours. The temperature is preferably between 0.degree.
C. and 30.degree. C., and the time from 15 minutes to 12 hours.
##STR20##
In Process (12) the thiadiazabicyclononanones (XXIV) are treated
with a catalytic amount of a base such as sodium methoxide, sodium
ethoxide, or potassium t-butoxide in a C.sub.1-5 alcohol such as
methanol, ethanol or t-butanol, at a temperature between 0.degree.
C. and the reflux temperature of the mixture from 15 minutes to
3 hours. Preferably at the reflux temperature of the mixture and
from 30 to 60 minutes. ##STR21##
Process (13) is carried out using 0.5 to 10 equivalents (preferably
0.8 to 3) of the hydrazines relative to the oxazines (XXXII). Examples
of hydrazines include hydrazine, alkyl hydrazines such as methyl,
ethyl, or t-butylhydrazine, and cyclic hydrazines such as 1-aminopyrrolidine.
The reaction proceeds without any solvents but is normally accelerated
by employing solvent.
Further reaction requires solvents such as aliphatic hydrocarbons
e,g, hexane, heptane, ligroin and petroleum ether, aromatic hydrocarbons
such as benzene, toluene, xylene, and chlorobenzene, halogenated
hydrocarbons such as chloroform and methylene chloride, ethers such
as diethyl ether, dioxane, and tetrahydrofuran, ketones such as
acetone and methyl ethyl ketones, nitriles such as acetonitrile
and isobutyronitrile, tertiary amines such as pyridine and N,N-dimethylaniline,
acid amides such as N,N-dimethyl-acetamide, N,N-dimethylformamide,
and N-methylpyrrolidone, sulfur containing compounds such as dimethylsulfoxide
and sulfolane, alcohols such as methanol, ethanol, propanol, and
butanol, water and the mixtures thereof.
The reaction temperature is usually from -30.degree. C. to 150.degree.
C., preferably from -10.degree. C. to the reflux temperature of
the reaction mixture. The reaction time requires normally from 10
minutes to 96 hours, preferably from 30 minutes to 48 hours. ##STR22##
In Process (14) the ether linkage is formed using the conditions
described in the first stage of Process (1). ##STR23##
Process (15) is carried out in a solvent such as dioxane, dimethylsulfoxide,
hexamethylphosphoric triamide or N,N-dimethylformamide in the presence
of a base such as sodium carbonate, potassium carbonate, sodium
hydroxide, potassium hydroxide, or sodium hydride. A number of aminating
agents may be used such as m24-dinitro-phenoxyamine; O-arylsulfonylhydroxyamines
such as 236-trimethyl- and triisopropyl-phenylhydroxyamine; O-picoylhydroxyamine;
and O-mesitylhydroxyamine. The reaction temperature is usually from
-30.degree. C. to 110.degree. C., and the reaction time is from
12 hours to 7 days. The reaction temperature is preferably from
20.degree. C. to 30.degree. C. The reaction time is preferably from
12 hours to 3 days. ##STR24##
Using Process (16) the isocyanate (III) may be used to form the
aminouracil (XXXIIIa) in a one pot synthesis without isolating the
uracil (XXXV). The uracil ring is formed by reacting the prepared
isocyanate (III) with an alkyl 3-amino-444-trifluoro-crotonate
and a base such as sodium hydride, sodium methoxide or sodium ethoxide,
in a solvent such as dimethylsulfoxide, N,N-dimethylformamide, benzene,
toluene, xylene, tetrahydrofuran, dioxane, or diethyl ether, at
temperatures usually from -50.degree. C. to 50.degree. C., with
a reaction time from 10 minutes to 14 hours. Preferably between
-30.degree. C. to 30.degree. C., with a reaction time of 15 minutes
to 6 hours. Aminating agents, such as 24-dinitro-phenoxyamine;
O-arylsulfonylhydroxy-amines such as 236-trimethyl- and triisopropyl-phenylhydroxyamine;
O-picoylhydroxyamine; and O-mesitylhydroxyamine are then introduced,
as described for Process (15). The reaction temperature is usually
from -30.degree. C. to 110.degree. C., and the reaction time is
from 12 hours to 7 days. The reaction temperature is preferably
from 20.degree. C. to 30.degree. C. The reaction time is preferably
from 12 hours to 3 days. ##STR25##
Using Process (17) a compound of formula (Q.sub.9) wherein A.sub.1
and/or A.sub.2 are/is a sulfur atom, can be prepared by reacting
a compound of the above formula (XXXIII) with a sulfurizing agent
such as Lawesson's reagent or phosphorus pentasulfide. Further sulfurization
may occur with prolonged heating and with excess reagent. The reaction
uses solvents such as benzene, toluene and xylene. The reaction
time is usually 2 to 12 hours, preferably 3 to 4 hours. The reaction
temperature is usually 0.degree. C. to 150.degree. C., preferably
between 60.degree. C. and the reflux temperature of the mixture.
##STR26##
In Process (18) the ether linkage is formed using the conditions
described in the first stage of Process (1). ##STR27##
Process (19) requires the reaction of the sodium or potassium salt
of an aromatic- or heterocyclic hydroxyl compound with the haloaromatic
uracil (XXXVIII). The reaction proceeds without any solvent but
is normally accelerated by employing solvent. These include toluene,
xylene, N,N-dimethylformamide, and dimethylsulfoxide, and a catalyst
is used such as copper, copper bronze, or a transition metal. The
temperature is usually from 0.degree. C. to 150.degree. C., and
the reaction time from 10 minutes to 72 hours. The temperature is
preferably from 150.degree. C. to the reflux temperature of the
mixture, and the time preferably 2 to 6 hours. ##STR28##
Process (20) shows how the uracil ring may be formed by reacting
the prepared isocyanate (III) with an alkyl 3-amino-444-trifluorocrotonate
and a base such as sodium hydride, sodium methoxide, sodium ethoxide,
or potassium t-butoxide, in a solvent such as dimethylsulfoxide,
N,N-dimethylformamide, benzene, toluene, xylene, tetrahydro-furan,
dioxane, or diethyl ether, at temperatures usually from -50.degree.
C. to 50.degree. C., with a reaction time from 10 minutes to 14
hours. Preferably from -30.degree. C. to 30.degree. C., with a reaction
time of 15 minutes to 6 hours. ##STR29##
Process (21) is carried out in two stages. The first step is the
preparation of N-phenyl-acetamide (XXXIX) using conventional methodology.
The second step is the cyclization to give the oxazines (XXXII).
This is carried out in solvents which are aliphatic hydrocarbons
such as hexane, heptane, ligroin, and petroleum ether, aromatic
hydrocarbons such as benzene, toluene, xylene, and chloro-benzene,
tertiary amines such as pyridine, and N,N-diethylaniline, acid amides
such as N,N-dimethylacetamide, N,N-dimethylformamide, and N-methylpyrrolidone,
sulfur containing compounds such as dimethylsulfoxide and sulfolane,
and organic acids such as formic acid, acetic acid, lactic acid,
and acetic anhydride. Preferably used are the above mentioned aliphatic
hydrocarbons, aromatic hydrocarbons and organic acids. The reaction
temperature is usually from 0.degree. C. to 200.degree. C. , preferably
from 20.degree. C. to the reflux temperature of the mixture. The
reaction time is from 10 minutes to 72 hours, preferably from 30
minutes to 24 hours. ##STR30##
Process (22) is carried out in two stages. The first step is the
formation of the phenolic oxazine (XL) using the methodology described
in Process (21). This is carried out in solvents which are aliphatic
hydrocarbons such as hexane, heptane, ligroin, and petroleum ether,
aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene,
tertiary amines such as pyridine, and N,N-diethylaniline, acid amides
such as N,N-dimethylacetamide, N,N-dimethylformamide, and N-methylpyrrolidone,
sulfur containing compounds such as dimethylsulfoxide and sulfolane,
and organic acids such as formic acid, acetic acid, lactic acid,
and acetic anhydride. Preferably used are the above mentioned aliphatic
hydrocarbons, aromatic hydrocarbons and organic acids. The reaction
temperature is usually from 0.degree. C. to 200.degree. C., preferably
from 20.degree. C. to the reflux temperature of the mixture. The
reaction time is from 10 minutes to 72 hours, preferably from 30
minutes to 24 hours.
The second step is carried out under the same conditions described
for Process (13). ##STR31##
Process (23) is carried out in two stages. The starting material
for the first step, carbamates (XLI), are prepared by conventional
methodology. These are treated with an alkyl 3-amino-444-trifluorocrotonate
under the conditions described for Process (20). The second step
is carried out under the same conditions described for Process (15).
##STR32##
In Process (24) the isocyanate (III) is treated with the hydrazono
compound (XLIII) under the conditions described for Process (20)
to give the desired product (XXXIII). ##STR33##
In Process (25) the ether linkage is formed using the conditions
described in the first stage of Process (1). ##STR34##
Process (26) uses two stages. The hydrazine (XXXXI) is formed from
compound (II) by reduction of the diazonium salt. Treatment with
a 11-dibromoketone in aqueous sodium acetate gives (XXXII) which
forms the pyridazinone (XXXXIII) when treated with a triphenylphosphorane.
Although some embodiments of the present invention are described
as follows, the scope of the present invention is not limited to
such an embodiment.
Preparation Examples for the compounds of the present invention
will be described. The preparation of 3-(4-chloro-2-fluoro-5-hydroxyphenyl)-6-trifluoromethyl-1234-tetra-hydr
opyrimidine-24-dione is described in U.S. Pat. No. 4859229. Lawesson's
reagent, [24-bis(4-methoxyphenyl)-13-dithia-24-diphosphetane-24-disulfide],
was obtained from Aldrich. |