Abstrict A stem/leaf desiccant for crop plants which comprises as an active
ingredient, a compound of formula (I): 1 wherein X represent CH
or nitrogen; Z represents halogen; A represents oxygen, sulfur,
or NH; R.sup.1 represents hydroxyl, C.sub.1-C.sub.7 alkoxy, C.sub.3-C.sub.7
alkenyloxy, C.sub.3-C.sub.7 alkynyloxy, C.sub.5-C.sub.7 cycloalkoxy,
{(C.sub.1-C.sub.7 alkoxy)carbonyl} C.sub.1-C.sub.3 alkoxy, (C.sub.1-C.sub.7
alkylamino)oxy, {di(C.sub.1-C.sub.7 alkyl)amino}oxy, (C.sub.3-C.sub.7
alkylideneamino)oxy, C.sub.1-C.sub.7 alkylamino, di(C.sub.1-C.sub.7
alkyl)amino, C.sub.3-C.sub.7 alkenylamino, C.sub.3-C.sub.7 alkynylamino,
C.sub.5-C.sub.7 cycloalkylamino, {(C.sub.1-C.sub.7 alkoxy)carbonyl}
C.sub.1-C.sub.3 alkylamino, or (C.sub.1-C.sub.7 alkoxy)amino; R.sup.2
is hydrogen or methyl; and R.sup.3 is hydrogen, halogen, C.sub.1-C.sub.3
alkyl, or C.sub.1-C.sub.3 alkoxy; a method for desiccating a crop
plant and a method for harvesting a crop by using the stem/leaf
desiccant.
Claims 1. A desiccant for a crop plant, which comprises as an active ingredient,
a compound of formula (I): 71wherein X is CH or nitrogen; Z is halogen;
A is oxygen, sulfur, or NH; R.sup.1 is hydroxyl, C.sub.1-C.sub.7
alkoxy, C.sub.3-C.sub.7 alkenyloxy, C.sub.3-C.sub.7 alkynyloxy,
C.sub.5-C.sub.7 cycloalkoxy, {(C.sub.1-C.sub.7 alkoxy)carbonyl}
C.sub.1-C.sub.3 alkoxy, (C.sub.1-C.sub.7 alkylamino)oxy, {di(C.sub.1-C.sub.7
alkyl)amino}oxy, (C.sub.3-C.sub.7 alkylideneamino)oxy, C.sub.1-C.sub.7
alkylamino, di(C.sub.1-C.sub.7 alkyl)amino, C.sub.3-C.sub.7 alkenylamino,
C.sub.3-C.sub.7 alkynylamino, C.sub.5-C.sub.7 cycloalkylamino, {(C.sub.1-C.sub.7
alkoxy)carbonyl} C.sub.1-C.sub.3 alkylamino, or (C.sub.1-C.sub.7
alkoxy)amino; R.sup.2 is hydrogen or methyl; and R.sup.3 is hydrogen,
halogen, C.sub.1-C.sub.3 alkyl, or C.sub.1-C.sub.3 alkoxy.
2. The desiccant for a potato, sunflower, soybean, rape or sorghum
plant, which comprises as the active ingredient, the compound of
formula (I) according to claim 1.
3. The desiccant for a potato plant, which comprises as the active
ingredient, the compound of formula (I) according to claim 1.
4. The desiccant for a sunflower plant, which comprises the active
ingredient, the compound of formula (I) according to claim 1.
5. A method for desiccating a crop plant, which comprises applying
the compound of formula (I) according to claim 1 to the crop plant
prior to harvest.
6. The method for desiccating a potato, sunflower, soybean, rape
or sorghum plant, which comprises applying the compound of formula
(I) according to claim 1 to the plant prior to harvest.
7. The method for desiccating a potato plant, which comprises applying
the compound of formula (I) according to claim 1 to a aboveground
part of the plants prior to harvest.
8. The method for desiccating a sunflower plant, which comprises
applying the compound of formula (I) according to claim 1 to a aboveground
part of the sunflower plant prior to harvest.
9. The method according to any one of claims 5 to 8 wherein the
compound of formula (I) is applied in an amount of 1 to 500 g per
1 ha.
10. A method for harvesting a crop, which comprises a step of applying
a compound of formula (I) according to claim 1 to the crop plant.
11. The method for harvesting a crop selecting from a group of
potato, sunflower, soybean, rape and sorghum, which comprises a
step of applying the compound of formula (I) according to claim
1 to the crop plant.
12. The method for harvesting a potato, which comprises a step
of applying the compound of formula (I) according to claim 1 to
the potato plant.
13. The method for harvesting a sunflower, which comprises a step
of applying the compound of formula (I) according to claim 1 to
the sunflower plant.
14. The method according to any one of claims 10 to 13 wherein
the compound of formula (I) is applied in an amount of 1 to 500
g per 1 ha.
15. Use of a compound of formula (I) according to claim 1 as a
desiccant.
Description TECHNICAL FIELD
[0001] The present invention relates to a stem/leaf desiccant which
is used before the harvest of crops such as potato, sunflower, soybean,
rape, sorghum and the like, for desiccating the aboveground part
of the plants.
BACKGROUND ART
[0002] Desiccants which desiccate the aboveground part of the plants
have been used to make harvest work of crops, such as potato, sunflower,
soybean, rape, sorghum and the like, easy. Especially in a case
of machine harvest, there is an advantage in an easy operation of
a harvest machine and the like. By desiccating aboveground parts
of the plants, an outbreak of plant diseases can be controlled.
The crops such as sunflower, the crops must be desiccated before
pressing oil from the crops after the harvest. In this case, by
spraying the desiccant, which desiccate the crop plants before the
harvest, to the plants, and lowering the water content of the seeds;
the drying cost before pressing oil can be decreased. Also, in a
case of soybean, rape and the like, by spraying the desiccant to
the plants and accelerating the ripeness of crops; the high-quality
harvesting which are uniformly ripen can be gained.
[0003] Namely, there are some advantages of desiccating these plants
before the harvest. Diquat has been used as a desiccant, however
there has been a great demand for higher-performance desiccant.
DISCLOSURE OF INVENTION
[0004] The present inventor has extensively sought for a novel
desiccant for potato, sunflower, soybean, rape, sorghum and the
like. As a result, he has found that compounds of formula (I): 2
[0005] wherein X is CH or nitrogen; Z is halogen; A is oxygen,
sulfur, or NH; R.sup.1 is hydroxyl, C.sub.1-C.sub.7 alkoxy, C.sub.3-C.sub.7
alkenyloxy, C.sub.3-C.sub.7 alkynyloxy, C.sub.5-C.sub.7 cycloalkoxy,
{(C.sub.1-C.sub.7 alkoxy)carbonyl} C.sub.1-C.sub.3 alkoxy, (C.sub.1-C.sub.7
alkylamino)oxy, {di(C.sub.1-C.sub.7 alkyl)amino}oxy, (C.sub.3-C.sub.7
alkylideneamino)oxy, C.sub.1-C.sub.7 alkylamino, di(C.sub.1-C.sub.7
alkyl)amino, C.sub.3-C.sub.7 alkenylamino, C.sub.3-C.sub.7 alkynylamino,
C.sub.5-C.sub.7 cycloalkylamino, {(C.sub.1-C.sub.7 alkoxy)carbonyl}
C.sub.1-C.sub.3 alkylamino or (C.sub.1-C.sub.7 alkoxy)amino; R.sup.2
is hydrogen or methyl; and R.sup.3 is hydrogen, halogen, C.sub.1-C.sub.3
alkyl, or C.sub.1-C.sub.3 alkoxy, have an excellent desiccant effect
for the crop plants, thereby completing the present invention. That
is, the present invention provides the desiccant, which comprise
compounds (I) as active ingredients and which are used for desiccating
aboveground parts of the plants, such as potato, sunflower, soybean,
rape, sorghum and the like, before the harvest of crops thereof
(hereinafter referred to as the present desiccant(s)).
BEST MODE FOR CARRYING OUT THE INVENTION
[0006] The present desiccant is typically used in a manner as described
below.
[0007] The application time of the present desiccant may change
because of the weather condition or the crop plants growth condition.
The present desiccant is usually applied when the ripening stage
of the plants come near after the vegetative growth of the plants,
which the present desiccant is going to be applied, has finished.
If the plants are potatoes, the present desiccant is preferably
applied between a time of foliage turning yellow and three days
before of the harvesting, more preferably between twenty-one days
before and three days before of the harvesting. If the plants are
sunflowers, the present desiccant is preferably applied when the
backside of the flowers turn yellow after the plants has been ripened;
or when a water content of the seeds ranges from 20 wt % to 50 wt
% when a water content is a reference. If the plants are soybeans,
the present desiccant is preferably applied between a time of leaves
turning brown and one-week before of the harvesting. If the plants
are rapes, the present desiccant is preferably applied when a color
of the seeds starts to change from green to brown.
[0008] The present desiccant is usually used in the form of various
formulations including emulsifiable concentrates, wettable powders,
flowables, and solutions, which can be prepared by mixing the compound
(I) with solid carriers, liquid carriers, or other bulking agents,
and if necessary, adding surfactants and other auxiliary agents
thereto. In these formulations, the compounds (I) are usually contained
each in an amount of 0.5% to 80% by weight, preferably 1% to 70%
by weight.
[0009] The solid carrier used in the formulation may include, for
example, the following materials in fine powder or granular form:
clays (e.g., kaolinite, diatomaceous earth, synthetic hydrated silicon
oxide, Fubasami clay, bentonite, acid clay); talc and other inorganic
minerals (e.g., sericite, quartz powder, sulfur powder, activated
carbon, calcium carbonate); and chemical fertilizers (e.g., ammonium
sulfate, ammonium phosphate, ammonium nitrate, ammonium chloride,
urea). The liquid carrier may include, for example, water; alcohols
(e.g., methanol, ethanol); ketones (e.g., acetone, methyl ethyl
ketone, cyclohexanone); aromatic hydrocarbons (e.g., toluene, xylene,
ethylbenzene, methylnaphthalene); non-aromatic hydrocarbons (e.g.,
hexane, cyclohexane, kerosine); esters (e.g., ethyl acetate, butyl
acetate); nitriles (e.g., acetonitrile, isobutyronitrile); ethers
(e.g., dioxane, diisopropyl ether); acid amides (e.g., dimethylformamide,
dimethylacetamide); and halogenated hydrocarbons (e.g., dichloroethane,
trichloroethylene).
[0010] The surfactant may include, for example, alkyl sulfate salts;
alkylsulfonic acid salts; alkylarylsulfonic acid salts; alkyl aryl
ethers and their polyoxyethylene derivatives; polyethylene glycol
ethers; polyol esters; and sugar alcohol derivatives.
[0011] The other auxiliary agents may include, for example, adhesive
agents and dispersing agents, such as casein, gelatin, polysaccharides
(e.g., powdered starch, gum arabic, cellulose derivatives, alginic
acid), lignin derivatives, and synthetic water-soluble polymers
(e.g., polyvinyl alcohol, polyvinyl pyrrolidone, polyacrylic acid);
and stabilizers such as PAP (isopropyl acid phosphate), BHT (26-di-tert-butyl-4-methylphenol)-
, BHA (2-/3-tert-butyl-4-methyoxyphenol), vegetable oils, mineral
oils, fatty acids, and fatty acid esters.
[0012] The present desiccant thus formulated is applied to plants
after diluted with water. The present desiccant can be expected
to have further enhanced effects by incorporation of tank mix adjuvants
in water used for dilution.
[0013] The application amounts of the compounds (I) may vary with
the formulations types, application times, and application places,
but are usually in the range of 1 to 500 g/ha, preferably 1 to 100
g/ha.
[0014] In the formula (I), halogen represented by Z refers to fluorine,
chlorine, bromine, or iodine;
[0015] C.sub.1-C.sub.7 alkoxy represented by R.sup.1 may include
methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy,
pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 22-dimethylpropoxy,
hexyloxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-methylpentyloxy,
4-methylpentyloxy, 12-dimethylbutoxy, 13-dimethylbutoxy, 23-dimethylbutoxy,
33-dimethylbutoxy, and heptyloxy;
[0016] C.sub.3-C.sub.7 alkenyloxy represented by R.sup.1 may include
2-propenyloxy, 3-butenyloxy, 4-pentenyloxy, 3-methyl-3-butenyloxy,
and 3-methyl-2-butenyloxy;
[0017] C.sub.3-C.sub.7 alkynyloxy represented by R.sup.1 may include
2-propynyloxy;
[0018] C.sub.5-C.sub.7 cycloalkoxy represented by R.sup.1 may include
cyclopentyloxy and cyclohexyloxy;
[0019] {(C.sub.1-C.sub.7 alkoxy)carbonyl} C.sub.1-C.sub.3 alkoxy
represented by R.sup.1 may include methoxycarbonylmethoxy, ethoxycarbonylmethoxy,
and 1-(methoxycarbonyl)-1-methylethoxy;
[0020] (C.sub.1-C.sub.7 alkylamino)oxy represented by R.sup.1 may
include (methylamino)oxy and (ethylamino)oxy;
[0021] {di(C.sub.1-C.sub.7 alkyl)amino}oxy represented by R.sup.1
may include (dimethylamino)oxy and (methylethylamino)oxy;
[0022] (C.sub.3-C.sub.7 alkylideneamino)oxy represented by R.sup.1
may include (isopropylideneamino)oxy;
[0023] C.sub.1-C.sub.7 alkylamino represented by R.sup.1 may include
methylamino, ethylamino, propylamino, isopropylamino, butylamino,
1-methylpropylamino, 2-methylpropylamino, pentylamino, 1-methylbutylamino,
2-methylbutylamino, 3-methylbutylamino, 22-dimethylpropylamino,
and hexylamino;
[0024] di(C.sub.1-C.sub.7 alkyl)amino represented by R.sup.1 may
include dimethylamino and diethylamino;
[0025] C.sub.3-C.sub.7 alkenylamino represented by R.sup.1 may
include 2-propenylamino;
[0026] C.sub.3-C.sub.7 alkynylamino represented by R.sup.1 may
include 2-propynylamino;
[0027] C.sub.5-C.sub.7 cycloalkylamino represented by R.sup.1 may
include cyclopentylamino and cyclohexylamino;
[0028] {(C.sub.1-C.sub.7 alkoxy)carbonyl} C.sub.1-C.sub.3 alkylamino
represented by R.sup.1 may include methoxycarbonylmethylamino;
[0029] (C.sub.1-C.sub.7 alkoxy)amino represented by R.sup.1 may
include methoxyamino, ethoxyamino, and isopropoxyamino;
[0030] halogen represented by R.sup.3 refers to fluorine, chlorine,
bromine, or iodine;
[0031] C.sub.1-C.sub.3 alkyl represented by R.sup.3 refers to methyl,
ethyl, propyl, or isopropyl; and
[0032] C.sub.1-C.sub.3 alkoxy represented by R.sup.3 refers to
methoxy, ethoxy, propoxy, or isopropoxy.
[0033] In the compounds of formula (I) used as the active ingredients
of the present desiccant, preferred are those wherein R.sup.1 is
methoxy or ethoxy; R.sup.3 is hydrogen; and/or Z is chlorine or
bromine.
[0034] Compounds (I) can be produced, for example, according to
production processes A to E as described below.
[0035] Production Process A 3
[0036] wherein X, Z, A, R.sup.2 and R.sup.3 are as defined above.
[0037] Compound (1-1) can be produced by reacting compound (V)
with a diazotizing agent (first step), followed by reaction with
a halide (second step).
[0038] The reaction in the first step is usually carried out at
a temperature range of -20.degree. C. to 20.degree. C., and the
reaction time is a moment to 5 hours.
[0039] The diazotizing agent used in the reaction may include nitrous
acid (prepared from nitrites such as sodium nitrite, and protonic
acids such as acetic acid and hydrochloric acid); nitrite esters
such as isoamyl nitrite and t-butyl nitrite. The reaction is usually
carried out by adding dropwise the diazotizing agent to a mixture
of compound (V) and a solvent such as acetic acid, acetonitrile,
or water, or preparing a diazotizing agent in the solvent.
[0040] The amounts of reagents are 1 mole of the diazotizing agent
relative to 1 mole of compound (V), which is a theoretical ratio,
but may suitably be changed depending upon the reaction conditions.
[0041] After the reaction in the first step, the reaction mixture
is usually used as the starting material in the second step, without
being subjected to separation.
[0042] The reaction in the second step is usually carried out in
the range of 0.degree. C. to 80.degree. C., and the reaction time
is a moment to 24 hours.
[0043] The halide used in the reaction may include fluorides (e.g.,
tetrafluoroboric acid), chlorides (e.g., copper (I) chloride), bromides
(e.g., copper (I) bromide), and iodides (e.g., potassium iodide).
The reaction is usually carried out by adding dropwise the reaction
mixture obtained in the first step to a mixture of a halide and
a solvent such as acetic acid, acetonitrile, or water.
[0044] The amounts of reagents are 1 mole of the halide relative
to 1 mole of compound (V), which is a theoretical ratio, but may
suitably be changed depending upon the reaction conditions.
[0045] After completion of the reaction, for example, the reaction
mixture is poured into water, which is then extracted with an organic
solvent, and the organic layer is concentrated to give a desired
compound.
[0046] Production Process B 4
[0047] wherein E is chlorine or bromine; and Z, A, R.sup.1 R.sup.2
and R.sup.3 are as defined above.
[0048] Compound (1-3) can be produced by reacting compound (VI)
with compound (XXI) in the presence of a base in a solvent.
[0049] The reaction temperature is usually in the range of 0.degree.
C. to 150.degree. C., and the reaction time is usually a moment
to 24 hours.
[0050] The base used in the reaction may include organic bases
such as pyridine, quinoline, N-methylmorpholine, 18-diazabicyclo
[5.4.0]undec-7-ene, 15-azabicylco[4.3.0]non-5-ene, 14-diazabicyclo[2.2.2]octane,
4-dimethylaminopyridine, N,N-dimethylaniline, N,N-diethylaniline,
triethylamine, tri-n-propylamine, and diisopropylethylamine; and
inorganic bases such as sodium carbonate, potassium carbonate, sodium
hydride, and potassium hydride.
[0051] The solvent used in the reaction may include aromatic hydrocarbons
such as toluene and xylene; aromatic halogenated hydrocarbons such
as chlorobenzene, dichlorobenzene, and benzotrifluride; ethers such
as diisopropyl ether, methyl t-butyl ether, dioxane, tetrahydrofuran,
ethylene glycol dimethyl ether, and diglym; ketones such as methyl
isobutyl ketone; esters such as ethyl acetate; nitro compounds such
as nitromethane; nitrites such as acetonitrile; amides such as N,N-dimethylformamide
and N-methyl-2-pyrollidone; sulfur compounds such as dimethylsulfoxide
and sulforane; and mixtures thereof.
[0052] The amounts of reagents are 1 mole of compound (XXI) and
1 mole of the base, relative to 1 mole of compound (VI), which is
a theoretical ratio, but may suitably be changed depending upon
the reaction conditions.
[0053] After completion of the reaction, for example, the reaction
mixture is poured into water, which is then extracted with an organic
solvent, and the organic layer is concentrated to give a desired
compound. The product may be purified by chromatography, recrystallization,
or any other technique.
[0054] Production Process C 5
[0055] wherein E.sup.1 is a leaving group such as iodine or methanesulfonyloxy,
and X, Z, A, R.sup.1 R.sup.2 and R.sup.3 are as defined above.
[0056] Compound (1-3) can be produced by reacting compound (XXV)
with compound (XXVI) in the presence of a base in a solvent.
[0057] The reaction temperature is usually in the range of 0.degree.
C. to 150.degree. C., and the reaction time is usually a moment
to 24 hours.
[0058] The base used in the reaction may include organic bases
such as pyridine, quinoline, N-methylmorpholine, 18-diazabicyclo
[5.4.0]undec-7-ene, 15-diazabicylco[4.3.0]non-5-ene, 14-diazabicyclo[2.2.2]octane,
4-dimethylaminopyridine, N,N-dimethylaniline, N,N-diethylaniline,
triethylamine, tri-n-propylamine, and diisopropylethylamine; and
inorganic bases such as sodium carbonate, potassium carbonate, sodium
hydride, and potassium hydride.
[0059] The solvent used in the reaction may include aromatic hydrocarbons
such as toluene and xylene; aromatic halogenated hydrocarbons such
as chlorobenzene, dichlorobenzene, and benzotrifluoride; ethers
such as diisopropyl ether, methyl t-butyl ether, dioxane, tetrahydrofuran,
ethylene glycol dimethyl ether, and diglym; ketones such as methyl
isobutyl ketone; esters such as ethyl acetate; nitro compounds such
as nitromethane; nitrites such as acetonitrile; amides such as N,N-dimethylformamide
and N-methyl-2-pyrollidone; sulfur compounds such as dimethylsulfoxide
and sulforane; and mixtures thereof.
[0060] The amounts of reagents are 1 mole of compound (XXVI) and
1 mole of the base, relative to 1 mole of compound (XXVI, which
is a theoretical ratio, but may suitably be changed depending upon
the reaction conditions.
[0061] After completion of the reaction, for example, the reaction
mixture is poured into water, which is then extracted with an organic
solvent, and the organic layer is concentrated to give a desired
compound. The product may be purified by chromatography, recrystallization,
or any other technique.
[0062] Production Process D 6
[0063] wherein X, Z, A, R.sup.1 R.sup.2 and R.sup.3 are as defined
above.
[0064] Compound (1-2) can be produced by reacting compound (1-1)
with compound (XX). The reaction may be carried out in the presence
of an acid or a base as a catalyst.
[0065] The reaction temperature is usually in the range of 20.degree.
C. to 150.degree. C., and the reaction time is usually a moment
to 24 hours.
[0066] The acid optionally used may include organic protonic acids
such as methanesulfonic acid; and inorganic protonic acids such
as sulfuric acid. The base may include organic bases such as pyridine;
and inorganic bases such as sodium carbonate.
[0067] The amounts of reagents are 1 mole to an excess of compound
(XX), relative to 1 mole of compound (1-1).
[0068] The reaction may involve the use of a solvent inert thereto.
In the reaction, the methanol formed as a by-product may be distilled
out of the reaction system, so that the rate of the reaction can
be increased.
[0069] After completion of the reaction, for example, the reaction
mixture is poured into water, which is then extracted with an organic
solvent, and the organic layer is concentrated to give a desired
compound. The product may be purified by chromatography, recrystallization,
or any other technique.
[0070] Production Process E
[0071] Compound (1-2) can also be produced by reacting compound
(1-4) with compound (XX) under the dehydration conditions. 7
[0072] wherein X, Z, A, R.sup.1 R.sup.2 and R.sup.3 are as defined
above.
[0073] Compound (V) can be produced by the process as shown below.
8
[0074] wherein X, A, R.sup.2 and R.sup.3 are as defined above.
[0075] First step: The step of producing compound (IV) from compound
(II) and compound (III).
[0076] Compound (IV) can be produced by reacting compound (II)
with compound (III) in the presence of a base in a solvent.
[0077] The reaction temperature is usually in the range of 0.degree.
C. to 150.degree. C., and the reaction time is usually a moment
to 24 hours.
[0078] The base used in the reaction may include organic bases
such as pyridine, quinoline, N-methylmorpholine, 18-diazabicyclo
[5.4.0]undec-7-ene, 15-diazabicylco[4.3.0]non-5-ene, 14-diazabicyclo[2.2.2]octane,
4-dimethylaminopyridine, N,N-dimethylaniline, N,N-diethylaniline,
triethylamine, tri-n-propylamine, and diisopropylethylamine; and
inorganic bases such as sodium carbonate, potassium carbonate, sodium
hydride, and potassium hydride.
[0079] The solvent used in the reaction may include aromatic hydrocarbons
such as toluene and xylene; ethers such as dioxane; amides such
as N,N-dimethylformamide and N-methyl-2-pyrollidone; sulfur compounds
such as dimethylsulfoxide and sulforane; and mixtures thereof.
[0080] The amounts of reagents are 1 mole of compound (II) and
1 mole of the base, relative to 1 mole of compound (III), which
is a theoretical ratio, but may suitably be changed depending upon
the reaction conditions.
[0081] After completion of the reaction, for example, the reaction
mixture is poured into water, which is then extracted with an organic
solvent, and the organic layer is concentrated to give a desired
compound. The product may be purified by chromatography, recrystallization,
or any other technique.
[0082] Second step: The step of producing compound (V) from compound
(IV).
[0083] Compound (V) can be produced by reacting compound (IV) with
iron powder in the presence of a protonic acid.
[0084] The reaction temperature is usually in the range of 0.degree.
C. to 100.degree. C., and the reaction time is usually a moment
to 24 hours.
[0085] The protonic acid used in the reaction may include organic
protonic acids such as acetic acid and propionic acid; and inorganic
protonic acids such as hydrochloric acid.
[0086] The amounts of reagents are 3 moles to an excess of the
iron powder and 3 moles to an excess of the acid, relative to 1
mole of compound (IV), which may suitably be changed depending upon
the reaction conditions.
[0087] The reaction may involve the use of a solvent inert thereto.
[0088] After completion of the reaction, for example, the reaction
mixture is filtered, and the filtrate is poured into water, which
is neutralized and then extracted with an organic solvent, and the
organic layer is concentrated to give a desired compound. The product
may be purified by chromatography, recrystallization, or any other
technique.
[0089] Compound (II) can be produced according to the process known
in the art.
[0090] Compound (III) can be produced by the process as shown below.
9
[0091] wherein X, A, R.sup.2 and R.sup.3 are as defined above.
[0092] First step: The step of producing compound (XV) from compound
(XIII) and compound (XIV).
[0093] Compound (XV) can be produced by reacting compound (XIII)
with compound (XIV) in the presence of a base in a solvent.
[0094] Second step: The step of producing compound (XVI) from compound
(XV).
[0095] Compound (XVI) can be produced by reducing compound (XV)
(e.g., by a technique such as iron reduction (Fe/acetic acid) or
hydrogenation (Pd-C/H.sub.2)).
[0096] Third step: The step of producing compound (XVII) from compound
(XVI).
[0097] Compound (XVII) can be produced by reacting compound (XVI)
with a diazotizing agent (e.g., nitrous acid (prepared from nitrites
such as sodium nitrite, and protonic acids such as acetic acid and
hydrochloric acid), nitrite esters such as isoamyl nitrite and t-butyl
nitrite), followed by reaction with acetic anhydride.
[0098] Fourth step: The step of producing compound (III) from compound
(XVII).
[0099] Compound (III) can be produced by selective hydrolysis of
compound (XVII).
[0100] Compound (XXV) can be produced according to the process
described in Reference Production Example 8 or 9.
[0101] For compounds (XX), (XXI), (XXVI), and (XIV), there can
be used commercially available compounds.
[0102] The present invention will hereinafter be further illustrated
by some specific examples; however, the present invention is not
limited only to these examples.
[0103] The following will describe production examples for the
compounds of formula (I), which are designated by their compound
numbers shown below in Tables 1 to 3.
[0104] Production Example 1: Production of Compound a-5 10
[0105] To a mixture of 0.93 g of methyl [2-{2-chloro-4-fluoro-5-[26-dioxo-
-4-(trifluoromethyl)-1236-tetrahydropyrim idin-1-yl]phenoxy}phenoxy]ace-
tate, 0.31 g of potassium carbonate, and 10 ml of N,N-dimethylformamide
was added 0.58 g of methyl iodide, and the mixture was stirred at
room temperature for 2 hours. Then 50 ml of diluted hydrochloric
acid was added, and the mixture was extracted with ethyl acetate.
The organic layer was washed with water, saturated aqueous sodium
chloride solution, dried over anhydrous sodium sulfate, and then
concentrated under reduced pressure. The residue was subjected to
silica gel column chromatography to give 0.82 g of methyl [2-{2-chloro-4-fluoro-5-[3-methyl-26-dioxo-4-(t-
rifluoromethyl)-1236-tetrah ydropyrimidin-1-yl]phenoxy}phenoxy]acetate
(compound a-5).
[0106] .sup.1H-NMR (CDCl.sub.3 250 MHz) .delta.(ppm): 3.49-3.50
(m, 3H), 3.73 (s, 3H), 4.66 (s, 2H), 6.28 (s, 1H), 6.76 (d, 1H,
J=6.6 Hz), 6.9-7.2 (m, 4H), 7.36 (d, 1H, J=8.9 Hz).
[0107] Production Example 2: Production of Compound a-6 11
[0108] To a mixture of 0.10 g of methyl [3-{2-chloro-4-fluoro-5-[26-dioxo-
-4-(trifluoromethyl)-1236-tetrahydropyrim idin-1-yl]phenoxy}-2-pyridylo-
xy]acetate, 1 ml of acetonitrile, and 31 mg of potassium carbonate
was added 32 mg of methyl iodide, and the mixture was stirred at
room temperature for 1.5 hours. Then, 64 mg of methyl iodide was
added, and the mixture was stirred at 50.degree. C. for 1 hour.
The mixture was filtered, and the filtrate was concentrated under
reduced pressure. The residue was subjected to silica gel column
chromatography to give 97 mg of methyl [3-{2-chloro-4-fluoro-5-[3-methyl-26-dioxo-4-(trifluoromethyl)-
-1236-tetrah ydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetate
(compound a-6).
[0109] Production Example 3: Production of Compound a-5 12
[0110] A mixture of 11.02 g of isoamyl nitrite and 45 ml of acetonitrile
was added dropwise to a mixture of 15.16 g of methyl [2-{2-amino-4-fluoro-5-[3-methyl-26-dioxo-4-(trifluoromethyl)-1236-te-
trah ydropyrimidin-1-yl]phenoxy}phenoxy]acetate, 6.21 g of copper
(I) chloride, 12.65 g of copper (II) chloride, and 250 ml of acetonitrile
at room temperature, and the mixture was stirred for 2 hours. The
reaction mixture was poured into 2% hydrochloric acid, and the mixture
was extracted with ethyl acetate. The organic layer was washed with
saturated aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate, and then concentrated. The residue was subjected
to silica gel column chromatography to give 13 g of methyl [2-{2-chloro-4-fluoro-5-[3-methyl-2-
,6-dioxo-4-(trifluoromethyl)-1236-tetrah ydropyrimidin-1-yl]phenoxy}phe-
noxy]acetate (compound a-5).
[0111] Production Example 4: Production of Compound a-6 13
[0112] First, 88 mg of isoamyl nitrite was added dropwise to a
mixture of 0.24 g of methyl [3-{2-amino-4-fluoro-5-[3-methyl-26-dioxo-4-(trifluorom-
ethyl)-1236-tetrah ydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetate,
99 mg of copper (I) chloride, 0.20 g of copper (II) chloride, and
2.5 ml of acetonitrile at room temperature, and the mixture was
stirred for 1 hour. The reaction mixture was poured into 2% hydrochloric
acid, and the mixture was extracted with ethyl acetate. The organic
layer was washed with saturated aqueous sodium chloride solution,
dried over anhydrous magnesium sulfate, and then concentrated. The
residue was subjected to silica gel column chromatography to give
0.21 g of methyl [3-{2-chloro-4-fluoro-5-[3-methyl-26-dioxo-4-(trifluoromethyl)-1236-t-
etrah ydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetate (compound
a-6).
[0113] m.p.: 52.2.degree. C.;
[0114] .sup.1H-NMR (CDCl.sub.3 300 MHz) .delta.(ppm): 3.50 (q,
3H, J=1.0 Hz), 3.70 (s, 3H), 4.90.(d, 1H, J=15.8 Hz), 4.97 (d, 1H,
J=15.8 Hz), 6.29 (s, 1H), 6.9-7.0 (m, 2H), 7.32 (dd, 1H, J=7.7
1.9 Hz), 7.37 (d, 1H, J=8.7 Hz), 7.92 (dd, 1H, J=4.9 1.9 Hz).
[0115] Production Example 5: Production of Compound b-6 14
[0116] First, 18 mg of isoamyl nitrite was added dropwise to a
mixture of 0.16 g of methyl 2-[3-{2-amino-4-fluoro-5-[3-methyl-26-dioxo-4-(trifluor-
omethyl)-1236-tetra hydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]propionat-
e, 63 mg of copper (I) chloride, 129 mg of copper (II) chloride,
and 1.5 ml of acetonitrile at 0.degree. C., and the mixture was
stirred for 1 hour and further stirred at room temperature for 1
hour. The reaction mixture was poured into a mixture of 1N hydrochloric
acid and ice, and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated aqueous sodium chloride
solution, dried over anhydrous magnesium sulfate, and then concentrated.
The residue was subjected to silica gel column chromatography to
give 0.12 g of methyl 2-[3-{2-chloro-4-fluoro-5-[3-methyl-26-dioxo-4-(trifluoromethyl)-1236-
-tetra hydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]propionate (compound
b-6) as a mixture of diastereoisomers.
[0117] .sup.1H-NMR (CDCl.sub.3 300 MHz) .delta.(ppm): 1.51 (d,
3/2H, J=7.0 Hz), 1.52 (d, 3/2H, J=7.0 Hz), 3.50 (s, 3H), 3.67 (s,
3H), 5.29 (q, 1/2H, J=7.0 Hz), 5.30 (q, 1/2H, J=7.0 Hz), 6.28 (s,
1/2H), 6.29 (s, 1/2H), 6.8-7.0 (m, 2H), 7.3-7.4 (m, 2H), 7.8-7.9
(m, 1H).
[0118] Production Example 6: Production of Compound b-10 15
[0119] A solution of 10.99 g of isoamyl nitrite in 10 ml of acetonitrile
was added to a mixture of 15.46 g of ethyl 2-[3-{2-amino-4-fluoro-5-[3-me-
thyl-26-dioxo-4-(trifluoromethyl)-1236-tetra hydropyrimidin-1-yl]pheno-
xy}-2-pyridyloxy]propionate, 6.19 g of copper (I) chloride, 12.61
g of copper (II) chloride, and 120 ml of acetonitrile at room temperature,
and the mixture was stirred for 3 hours. The reaction mixture was
poured into a mixture of ice and hydrochloric acid, and the mixture
was extracted with ethyl acetate. The organic layer was washed with
saturated aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate, and then concentrated. The residue was subjected
to silica gel column chromatography to give 13.16 g of ethyl 2-[3-{2-chloro-4-fluoro-5-[3-meth-
yl-26-dioxo-4-(trifluoromethyl)-123 6-tetrahydropyrimidin-1-yl]phenoxy-
}-2-pyridyloxy]propionate (compound b-10).
[0120] Production Example 7: Production of Compound a-8 16
[0121] First, 92 mg of isoamyl nitrite was added dropwise to a
mixture of 0.26 g of methyl [3-{2-amino-4-fluoro-5-[3-methyl-26-dioxo-4-(trifluorom-
ethyl)-12 36-tetrah ydropyrimidin-1-yl]phenoxy}-2-pyridylthio]acetate,
0.10 g of copper (I) chloride, 0.21 g of copper (II) chloride, and
2.5 ml of acetonitrile at room temperature, and the mixture was
stirred for 1 hour. The reaction mixture was poured into 2% hydrochloric
acid, and the mixture was extracted with ethyl acetate. The organic
layer was washed with saturated aqueous sodium chloride solution,
dried over anhydrous magnesium sulfate, and then concentrated. The
residue was subjected to silica gel column chromatography to give
0.10 g of methyl [3-{2-chloro-4-fluoro-5-[3-methyl-26-dioxo-4-(trifluoromethyl)-1236-t-
etrah ydropyrimidin-1-yl]phenoxy}-2-pyridylthio]acetate (compound
a-8).
[0122] .sup.1H-NMR (CDCl.sub.3 300 MHz) .delta.(ppm): 3.54 (s,
3H), 3.75 (s, 3H), 4.01 (s, 2H), 6.33 (s, 1H), 6.9-7.0 (m, 3H),
7.42 (d, 1H, J=9.0 Hz), 8.20 (dd, 1H, J=4.1 2.2 Hz).
[0123] Production Example 8: Production of Compound a-108 17
[0124] First, isoamyl nitrite is added dropwise to a mixture of
methyl [3-{2-amino-4-fluoro-5-[3-methyl-26-dioxo-4-(trifluoromethyl)-1236-te-
trah ydropyrimidin-1-yl]phenoxy}-6-chloro-2-pyridyloxy]acetate,
copper (I) chloride, copper (II) chloride, and acetonitrile at room
temperature, and the mixture is stirred for 1 hour. The reaction
mixture is poured into 2% hydrochloric acid, and the mixture is
extracted with ethyl acetate. The organic layer is washed with saturated
aqueous sodium chloride solution, dried over anhydrous magnesium
sulfate, and then concentrated. The residue is subjected to silica
gel column chromatography to give methyl [3-{2-chloro-4-fluoro-5-[3-methyl-26-dioxo-4-(trifluoromethyl)-1236-t-
etrah ydropyrimidin-1-yl]phenoxy}-6-chloro-2-pyridyloxy]acetate
(compound a-108).
[0125] Production Example 9: Production of Compound a-118 18
[0126] First, isoamyl nitrite is added dropwise to a mixture of
methyl [3-{2-amino-4-fluoro-5-[3-methyl-26-dioxo-4-(trifluoromethyl)-1
236-tetrah ydropyrimidin-1-yl]phenoxy}-6-methoxy-2-pyridyloxy]acetate,
copper (I) chloride, copper (II) chloride, and acetonitrile at room
temperature, and the mixture is stirred for 1 hour. The reaction
mixture is poured into 2% hydrochloric acid, and the mixture is
extracted with ethyl acetate. The organic layer is washed with saturated
aqueous sodium chloride solution, dried over anhydrous magnesium
sulfate, and then concentrated. The residue is subjected to silica
gel column chromatography to give methyl [3-{2-chloro-4-fluoro-5-[3-methyl-26-dioxo-
-4-(trifluoromethyl)-1236-tetrah ydropyrimidin-1-yl]phenoxy}-6-methoxy--
2-pyridyloxy]acetate (compound a-118).
[0127] Production Example. 10: Production of Compound b-5 19
[0128] First, 0.23 g of 2-{2-chloro-4-fluoro-5-[3-methyl-26-dioxo-4-(trif-
luoromethyl)-1236-tetrahy dropyrimidin-1-yl]phenoxy}phenol was
dissolved in 6 ml of N,N-dimethylformamide, to which 0.22 g of potassium
carbonate was added and 0.13 g of methyl 2-bromopropionate was added
under stirring at room temperature, and the mixture was stirred
at 80.degree. C. for 3 hours. The reaction mixture was cooled to
room temperature and then poured into ice water, and the mixture
was extracted with ethyl acetate. The organic layer was washed with
saturated aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate, and then concentrated. The residue was subjected
to silica gel column chromatography to give 0.23 g of methyl 2-[2-{2-chloro-4-fluoro-5-[3-meth-
yl-26-dioxo-4-(trifluoromethyl)-1236-tetra hydropyrimidin-1-yl]phenoxy-
}phenoxy]propionate (compound b-5).
[0129] .sup.1H-NMR (CDCl.sub.3 250 MHz) .delta.(ppm): 1.47 (d,
3H, J=6.8 Hz), 3.50 (q, 3H, J=0.7 Hz), 3.6-3.8 (m, 3H), 4.6-4.8
(m, 1H), 6.28 (s, 1H), 6.7-6.8 (m, 1H), 6.8-6.9 (m, 1H), 6.9-7.1
(m, 1H), 7.1-7.2 (m, 2H), 7.3-7.4 (m, 1H).
[0130] Production Example 11: Production of Compound a-121 20
[0131] First, 0.20 g of 2-{2-chloro-4-fluoro-5-[3-methyl-26-dioxo-4-(trif-
luoromethyl)-1236-tetrahy dropyrimidin-1-yl]phenoxy}phenol was
dissolved in 2 ml of N,N-dimethylformamide, to which 0.083 g of
potassium carbonate was added, and the mixture was stirred at room
temperature for 50 minutes. Then, 0.077 g of t-butyl chloroacetate
was added, and the mixture was stirred at 40.degree. C. to 60.degree.
C. for 2 hours. After left for cooling, ice water was poured into
the reaction mixture, and after addition of ethyl acetate and saturated
aqueous sodium chloride solution, the mixture was subjected to phase
separation. The organic layer was washed with saturated aqueous
sodium chloride solution, dried over magnesium sulfate, and then
concentrated. The residue was subjected to silica gel column chromatography
(eluent: n-hexane/ethyl acetate=6/1) to give 10.39 g of t-butyl
[2-{2-chloro-4-fluoro-5-[3-methyl-26-dioxo-4-- (trifluoromethyl)-1236-tetrah
ydropyrimidin-1-yl]phenoxy}phenoxy]acetat- e (compound a-121).
[0132] .sup.1H-NMR (CDCl.sub.3 250 MHz) .delta.(ppm): 1.44 (s,
9H), 3.49 (d, 3H, J=1.1 Hz), 4.53 (s, 2H), 6.27 (s, 1H), 6.80 (d,
1H, J=6.6 Hz), 6.8-7.2 (m, 4H), 7.35 (d, 1H, J=8.9 Hz);
[0133] m.p.: 55.6.degree. C.
[0134] The physical properties of compounds produced by the same
process as described in Production Examples 10 and 11 are shown
below. 21
[0135] Ethyl 2-[2-{2-chloro-4-fluoro-5-[3-methyl-26-dioxo-4-(trifluoromet-
hyl)-1236-tetra hydropyrimidin-1-yl]phenoxy}phenoxy]propionate
(compound b-9)
[0136] .sup.1H-NMR (CDCl.sub.3 250 MHz) .delta.(ppm): 1.23 (t,
3H, J=7.1 Hz), 1.47 (d, 3H, J=6.8 Hz), 3.50 (s, 3H), 4.1-4.3 (m,
2H), 4.6-4.8 (m, 1H), 6.3-6.4 (m, 1H), 6.7-7.0 (m, 3H), 7.0-7.2
(m, 2H), 7.3-7.4 (m, 1H). 22
[0137] Ethyl [2-{2-chloro-4-fluoro-5-[3-methyl-26-dioxo-4-(trifluoromethy-
l)-1236-tetrah ydropyrimidin-1-yl]phenoxy}phenoxy]acetate (compound
a-9)
[0138] .sup.1H-NMR (CDCl.sub.3 300 MHz) .delta.(ppm): 1.26 (t,
3H, J=7.1 Hz), 3.50 (s, 3H), 4.19 (q, 2H, J=7.2 Hz), 4.64 (s, 2H),
6.28 (s, 1H), 6.7-6.8 (m, 1H), 6.9-7.2 (m, 4H), 7.36 (d, 1H, J=8.8
Hz).
[0139] Production Example 12: Production of Compound a-28 23
[0140] A mixture of 0.30 g of methyl [3-{2-chloro-4-fluoro-5-[3-methyl-26-
-dioxo-4-(trifluoromethyl)-1236-tetrah ydropyrimidin-1-yl]phenoxy}-2-py-
ridyloxy]acetate (compound a-6), 0.06 g of sodium carbonate, and
3.0 ml of cyclopentanol was stirred at 100.degree. C. for 1.5 hours
and then at 120.degree. C. for 2 hours. The reaction mixture was
cooled to room temperature and then poured into water, and the mixture
was extracted with ethyl acetate. The organic layer was washed with
saturated aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate, and then concentrated. The residue was subjected
to silica gel column chromatography to give 0.15 g of cyclopentyl
[3-{2-chloro-4-fluoro-5-[3-m- ethyl-26-dioxo-4-(trifluoromethyl)-1236-tetrah
ydropyrimidin-1-yl]phen- oxy}-2-pyridyloxy]acetate (compound a-28).
[0141] Production Example 13: Production of Compound a-10 24
[0142] A mixture of 0.60 g of methyl [3-{2-chloro-4-fluoro-5-[3-methyl-26-
-dioxo-4-(trifluoromethyl)-1236-tetrah ydropyrimidin-1-yl]phenoxy}-2-py-
ridyloxy]acetate (compound a-6), 0.13 g of sodium carbonate, and
7.0 ml of ethanol was heated at reflux for 2 hours. After cooling
to room temperature, the solvent was distilled out under reduced
pressure, and the residue was subjected to silica gel chromatography
to give 0.55 g of ethyl [3-{2-chloro-4-fluoro-5-[3-methyl-26-dioxo-4-(trifluoromethyl)-12-
,36-tetrah ydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetate (compound
a-10).
[0143] .sup.1H-NMR (CDCl.sub.3 250 MHz) .delta.(ppm): 1.25 (t,
3H, J=7.1. Hz), 3.50 (q, 3H, J=1.2 Hz), 4.16 (q, 2H, J=7.1 Hz),
4.88 (d, 1H, J=15.9 Hz), 4.96 (d, 1H, J=15.9 Hz), 6.29 (s, 1H),
6.9-7.0 (m, 2H), 7.3-7.4 (m, 2H), 7.9-8.0 (m, 1H).
[0144] Production Example 14: Production of Compound a-14 25
[0145] A mixture of 0.60 g of methyl [3-{2-chloro-4-fluoro-5-[3-methyl-26-
-dioxo-4-(trifluoromethyl)-1236-tetrah ydropyrimidin-1-yl]phenoxy}-2-py-
ridyloxy]acetate (compound a-6), 0.13 g of sodium carbonate, and
7.0 ml of n-propanol was stirred under reflux for 2 hours. After
cooling to room temperature, the solvent was distilled out under
reduced pressure, and the residue was subjected to silica gel column
chromatography to give propyl [3-{2-chloro-4-fluoro-5-[3-methyl-26-dioxo-4-(trifluoromethyl)-1-
236-tetrah ydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetate (compound
a-14).
[0146] .sup.1H-NMR (CDCl.sub.3 300 MHz) .delta.(ppm): 0.89 (t,
3H, J=7.3 Hz), 1.63 (qt, 2H, J=7.3 6.5 Hz), 3.50 (q, 3H, J=0.8
Hz), 4.06 (t, 2H, J=6.5 Hz), 4.89 (d, 1H, J=16.0 Hz), 4.97 (d, 1H,
J=16.0 Hz), 6.28 (s, 1H), 6.91 (dd, 1H, J=7.8 5.0 Hz), 6.93 (d,
1H, J=6.5 Hz), 7.31 (dd, 1H, J=7.8 1.6 Hz), 7.36 (d, 1H, J=8.9
Hz), 7.91 (dd, 1H, J=5.0 1.6 Hz).
[0147] Production Example 15: Production of Compound a-20 26
[0148] A mixture of 0.30 g of methyl [3-{2-chloro-4-fluoro-5-[3-methyl-26-
-dioxo-4-(trifluoromethyl)-1236-tetrah ydropyrimidin-1-yl]phenoxy}-2-py-
ridyloxy]acetate (compound a-6), 0.06 g of sodium carbonate, and
3.0 ml of n-pentanol was stirred at 100.degree. C. for 1.5 hours.
After cooling to room temperature, the reaction mixture was poured
into water, and the mixture was extracted with ethyl acetate. The
organic layer was washed with saturated aqueous sodium chloride
solution, dried over anhydrous magnesium sulfate, and then concentrated.
The residue was subjected to silica gel column chromatography to
give 0.07 g of pentyl [3-{2-chloro-4-fluoro-5-[3-methyl-26-dioxo-4-(trifluoromethyl)-1236-t-
etrah ydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetate (compound
a-20).
[0149] .sup.1H-NMR (CDCl.sub.3 300 MHz) .delta.(ppm) 0.88 (t,
3H, J=6.6 Hz), 1.2-1.4 (m, 4H), 1.5-1.7 (m, 2H), 3.50 (q, 3H, J=1.0
Hz), 4.0-4.2 (m, 2H), 4.8-5.1 (m, 2H), 6.29 (s, 1H), 6.9-7.0 (m,
2H), 7.28 (dd, 1H, J=7.9 1.4 Hz), 7.37 (d, 1H, J=9.0 Hz), 7.91
(dd, 1H, J=4.9 1.4 Hz).
[0150] Production Example 16: Production of Compound b-19 27
[0151] First, 2-[2-{2-chloro-4-fluoro-5-[3-methyl-26-dioxo-4-(trifluorome-
thyl)-12 36-tetra hydropyrimidin-1-yl]phenoxy}phenoxy]propionic
acid (compound b-1) is dissolved in tetrahydrofuran, to which thionyl
chloride is added under stirring, and the mixture is heated and
stirred under reflux. After left for cooling and the subsequent
concentration, the residue is dissolved in tetrahydrofuran (hereinafter
referred to as solution A). Tetrahydrofuran is added to 1-pentyl
alcohol, to which solution A id added and pyridine is then added.
After stirring at room temperature, 2% aqueous hydrochloric acid
is added to the reaction mixture, and the mixture is extracted with
ethyl acetate. The organic layer is washed with saturated aqueous
sodium chloride solution, dried over magnesium sulfate, and then
concentrated. The residue is subjected to silica gel column chromatography
(eluent: hexane/ethyl acetate=5/1) to give pentyl 2-[2-{2-chloro-4-fluoro-5-[3-methyl-26-dioxo-4-(trifluoromet-
hyl)-1236-tetra hydropyrimidin-1-yl]phenoxy}phenoxy]propionate
(compound b-19).
[0152] Production Example 17: Production of Compound a-21 28
[0153] First, 1.0 g of [2-{2-chloro-4-fluoro-5-[3-methyl-26-dioxo-4-(trif-
luoromethyl)-1236-tetrah ydropyrimidin-1-yl]phenoxy}phenoxy]acetic
acid (compound a-1) was dissolved in tetrahydrofuran, to which 0.7
ml of thionyl chloride was added under stirring, and the mixture
was heated and stirred under reflux for 2 hours. After left for
cooling and the subsequent concentration, the residue was dissolved
in 3 ml of tetrahydrofuran (hereinafter referred to as solution
B). Then, 0.7 ml of tetrahydrofuran was added to 0.05 g of allyl
alcohol, to which a third part of solution B was added and 0.17
ml of pyridine was then added. After stirring at room temperature
for 2 hours, 2% aqueous hydrochloric acid was poured into the reaction
mixture, and the mixture was extracted with ethyl acetate. The organic
layer was washed with saturated aqueous sodium chloride solution,
dried over magnesium sulfate, and then concentrated. The residue
was subjected to silica gel column chromatography (eluent: hexane/ethyl
acetate=5/1) to give 0.08 g of allyl [2-{2-chloro-4-fluoro-5-[3-methyl-26-dioxo-4-(trifluoromethyl)-1236-t-
etrah ydropyrimidin-1-yl]phenoxy}phenoxy]acetate (compound a-21).
[0154] .sup.1H-NMR (CDCl.sub.3 300 MHz) .delta.(ppm): 3.50 (d,
3H, J=1.2 Hz), 4.62-4.64 (m, 2H), 4.68 (s, 2H), 5.22-5.32 (m, 2H),
5.8-6.0 (m, 1H), 6.28 (s, 1H), 6.76 (d, 1H, J=6.5 Hz), 6.91-7.14
(m, 4H), 7.35 (d, 1H, J=8.6 Hz).
[0155] Production Example 18: Production of Compound a-123 29
[0156] First, 1.5 g of [2-{2-chloro-4-fluoro-5-[3-methyl-26-dioxo-4-(trif-
luoromethyl)-1236-tetrah ydropyrimidin-1-yl]phenoxy}phenoxy]acetic
acid (compound a-1) was dissolved in 6 ml, to which 1 ml of thionyl
chloride was added under stirring, and the mixture was heated and
stirred under reflux for 2 hours and 10 minutes. After left for
cooling and the subsequent concentration, the residue was dissolved
in 3 ml of tetrahydrofuran (hereinafter referred to as solution
C). Then, 1 ml of tetrahydrofuran was added to 0.273 g of isobutyl
alcohol, to which a third part of solution C was added and 0.25
ml of pyridine was then added. After stirring at room temperature
for 2 hours, 2% aqueous hydrochloric acid was poured into the reaction
mixture, to which ethyl acetate was added, and the mixture was subjected
to phase separation. The organic layer was washed with saturated
aqueous sodium chloride solution, dried over magnesium sulfate,
and then concentrated. The residue was subjected to silica gel column
chromatography (eluent: hexane/ethyl acetate=6/1) to give 0.34 g
of isobutyl [2-{2-chloro-4-fluoro-5-[3-methyl- -26-dioxo-4-(trifluoromethyl)-1236-tetrah
ydropyrimidin-1-yl]phenoxy}p- henoxy]acetate (compound a-123).
[0157] .sup.1H-NMR (CDCl.sub.3 250 MHz) .delta.(ppm): 0.89 (d,
6H, J=6.7 Hz), 1.8-2.0 (m, 1H), 3.50 (d, 3H, J=1.2 Hz), 3.92 (d,
2H, J=6.7 Hz), 4.67 (s, 2H), 6.28 (s, 1H), 6.77 (d, 1H, J=6.6 Hz),
6.85-7.15 (m, 4H), 7.36 (d, 1H, J=8.9 Hz).
[0158] Production Example 19: Production of Compound a-104 30
[0159] First, 0.13 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride was added to a mixture of 0.30 g of [3-{2-chloro-4-fluoro-5-
-[3-methyl-26-dioxo-4-(trifuoromethyl)-1236-tetrah ydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetic
acid (compound a-2), 56 mg of o-methylhydroxylamine, 68 mg of triethylamine,
and 2 ml of N,N-dimethylformamide at room temperature, and the mixture
was stirred for 2 hours. The mixture was poured into water, and
the mixture was extracted with ethyl acetate. The organic layer
was dried over anhydrous magnesium sulfate and then concentrated.
The residue was subjected to silica gel column chromatography to
give 90 mg of N-methoxy-[3-{2-chloro-- 4-fluoro-5-[3-methyl-26-dioxo-4-(trifluoromethyl)-1
236-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetamide (compound
a-104).
[0160] .sup.1H-NMR (CDCl.sub.3 300 MHz) .delta.(ppm): 3.52 (s,
3H), 3.74 (s, 3H), 4.87 (s, 2H), 6.32 (s, 1H), 6.71 (d, 1H, J=6.0
Hz), 6.99 (dd, 1H, J=7.6 5.0 Hz), 7.38 (dd, 1H, J=7.6 1.7 Hz),
7.44 (d, 1H, J=8.7 Hz), 8.00 (dd, 1H, J=5.0 1.7 Hz), 8.7-9.0 (bs,
1H).
[0161] Production Example 20: Production of Compound a-32 31
[0162] First, 0.13 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride was added to a mixture of 0.30 g of [3-{2-chloro-4-fluoro-5-
-[3-methyl-26-dioxo-4-(trifluoromethyl)-1236-tetrah ydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetic
acid (compound a-2), 60 mg of methyl glycolate, and 2 ml of N,N-dimethylformamide
at room temperature, and the mixture was stirred for 1.5 hours.
The mixture was poured into water, and the mixture was extracted
with ethyl acetate. The organic layer was dried over anhydrous magnesium
sulfate and then concentrated. The residue was subjected to silica
gel column chromatography to give 0.18 g of methyl [3-{2-chloro-4-fluoro-5-[3-methyl-
-26-dioxo-4-(trifluoromethyl)-1236-tetrah ydropyrimidin-1-yl]phenoxy}--
2-pyridyloxy]acetoxyacetate (compound a-32).
[0163] .sup.1H-NMR (CDCl.sub.3 300 MHz) .delta.(ppm): 3.50 (s,
3H), 3.74 (s, 3H), 4.65 (s, 2H), 5.01 (d, 1H, J=16.2 Hz), 5.09 (d,
1H, J=16.2 Hz), 6.28 (s, 1H), 6.88 (d, 1H, J=6.7 Hz), 6.93 (dd,
1H, J=7.8 4.9 Hz), 7.32 (dd, 1H, J=7.8 1.4 Hz), 7.37 (d, 1H, J=9.0
Hz), 7.93 (dd, 1H, J=4.9 1.4 Hz).
[0164] Production Example 21: Production of Compound a-98 32
[0165] First, 0.13 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide
hydrochloride was added to a mixture of 0.30 g of [3-{2-chloro-4-fluoro-5-
-[3-methyl-26-dioxo-4-(trifluoromethyl)-1236-tetrah ydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetic
acid (compound a-2), 49 mg of acetone oxime, and 2 ml of N,N-dimethylformamide
at room temperature, and the mixture was stirred for 2 hours. The
mixture was poured into water, and the mixture was extracted with
ethyl acetate. The organic layer was dried over anhydrous magnesium
sulfate and then concentrated. The residue was subjected to silica
gel column chromatography to give 0.16 g of acetone O-[3-{2-chloro-4-fluoro-5-[3-met-
hyl-26-dioxo-4-(trifluoromethyl)-1236-tetr ahydropyrimidin-1-yl]phenox-
y}-2-pyridyloxy]acetyloxime (compound a-98).
[0166] .sup.1H-NMR (CDCl.sub.3 300 MHz) .delta.(ppm): 1.94 (s,
3H), 2.01 (s, 3H), 3.49 (s, 3H), 5.0-5.2 (m, 2H), 6.27 (s, 1H),
6.92 (dd, 1H, J=7.8 4.9 Hz), 6.98 (d, 1H, J=6.5 Hz), 7.3-7.4 (m,
2H), 7.92 (d, 1H, J=4.9 Hz).
[0167] The following will describe production examples for intermediates
in the production of compounds (I).
[0168] Reference Production Example 1
[0169] Step 1: 33
[0170] A mixture of 4.05 g of 2-benzyloxyphenol and 9.5 ml of N,N-dimethylformamide
was added dropwise to a mixture of 0.80 g of sodium hydride and
20 ml of N,N-dimethylformamide under ice cooling, and the mixture
was stirred for 30 minutes. A mixture of 7.1 g of 25-difluoro-4-[3-methyl-26-dioxo-4-(trifluoromethyl)-1236-tetrahydro-
pyri midin-1-yl]nitrobenzene and 17 ml of N,N-dimethylformamide
was added dropwise at the same temperature, and the mixture was
stirred for 1 hour. The reaction mixture was poured into ice water,
and the mixture was extracted with ethyl acetate. The organic layer
was washed once with 1N hydrochloric acid and once with saturated
aqueous sodium chloride solution, dried over anhydrous magnesium
sulfate, and then concentrated. The residue was subjected to silica
gel column chromatography to give 8.6 g of 2-(2-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-26-dioxo-4-(trifluorome-
thyl)-1 236-tetrahydropyrimidin-1-yl]nitrobenzene.
[0171] .sup.1H-NMR (CDCl.sub.3 250 MHz) .delta.(ppm): 3.52 (q,
3H, J=1.1 Hz), 5.01 (s, 2H), 6.31 (s, 1H), 6.81 (d, 1H, J=6.0 Hz),
6.9-7.1 (m, 2H), 7.1-7.4 (m, 7H), 7.78 (d, 1H, J=8.7 Hz).
[0172] Step 2: 34
[0173] To a mixture of 8.6 g of iron powder, 27 ml of acetic acid,
and 2.7 ml of water was added dropwise a solution of 8.6 g of 2-(2-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-26-dioxo-4-(trifluoromethyl)-
-1 236-tetrahydropyrimidin-1-yl]nitrobenzene in 23 ml of acetic
acid, while the temperature of the reaction mixture was kept at
35.degree. C. or lower. After completion of the dropwise addition,
the reaction mixture was stirred for 2 hours and then filtered through
Celite. The filtrate was diluted with ethyl acetate. The mixture
was neutralized with saturated aqueous sodium bicarbonate solution.
The organic layer was washed with saturated aqueous sodium chloride
solution, dried over anhydrous magnesium sulfate, and then concentrated.
The residue was subjected to silica gel column chromatography to
give 6.46 g of 2-(2-benzyloxyphenoxy)-5-fluoro4-[3-methyl-26-dioxo-4-(trifluoromethyl)--
12 36-tetrahydropyrimidin-1-yl]aniline.
[0174] .sup.1H-NMR (CDCl.sub.3 250 MHz) .delta.(ppm): 3.50 (q,
3H, J=1.2 Hz), 5.06 (s, 2H), 6.29 (s, 1H), 6.57 (dd, 1H, J=8.5
1.6 Hz), 6.9-7.0 (m, 1H), 7.0-7.1 (m, 3H), 7.2-7.4 (m, 6H).
[0175] Step 3: 35
[0176] First, 4.46 g of isoamyl nitrite was added dropwise to a
mixture of 6.46 g of 2-(2-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-2
6 -dioxo-4-(trifluoromethyl)-1 236-tetrahydropyrimidin-1-yl]aniline,
2.45 g of copper (I) chloride, 5.04 g of copper (II) chloride, and
90 ml of acetonitrile at room temperature, and the mixture was stirred
for 1 hour. The reaction mixture was poured into 2% hydrochloric
acid, and the mixture was extracted with ethyl acetate. The organic
layer was washed with saturated aqueous sodium chloride solution,
dried over anhydrous magnesium sulfate, and then concentrated. The
residue was subjected to silica gel column chromatography to give
4.6 g of ([2-{2-chloro-4-fluoro-- 5-[3-methyl-26-dioxo-4-(trifluoromethyl)-1236-tetrah
ydropyrimidin-1-yl]phenoxy}phenoxy]methyl)benzene.
[0177] m.p.: 50.8.degree. C.
[0178] Step 4: 36
[0179] To 4.5 g of ([2-{2-chloro-4-fluoro-5-[3-methyl-26-dioxo-4-(trifluo-
romethyl)-1236-tetrah ydropyrimidin-1-yl]phenoxy}phenoxy]methyl)benzene
were added 230 ml of ethyl acetate and 0.46 g of 10% palladium/carbon,
and the mixture was stirred at room temperature under an atmosphere
of hydrogen gas for 5 hours. The gas in the atmosphere on the reaction
system was replaced with nitrogen gas, and the reaction mixture
was filtered through Celite. The filtrate was concentrated to give
3.57 g of 2-{2-chloro-4-fluoro-5-[3-methyl-26-dioxo-4-(trifluoromethyl)-1
236-tetrahy dropyrimidin-1-yl]phenoxy}phenol.
[0180] m.p.: 55.4.degree. C.
[0181] Reference Production Example 2 37
[0182] First, 0.365 g of methyl 2-[2-{2-chloro-4-fluoro-5-[3-methyl-26-di-
oxo-4-(trifluoromethyl)-1236-tetra hydropyrimidin-1-yl]phenoxy}phenoxy]-
propionate was dissolved in 4 ml of 14-dioxane, to which a mixed
solution of 1 ml of concentrated hydrochloric acid and 1 ml of water
was added under stirring, and the mixture was heated and stirred
under reflux for 5 hours and 45 minutes. The reaction mixture was
then left for cooling, into which ice water was poured, and after
addition of ethyl acetate and saturated aqueous sodium chloride
solution, the mixture was subjected to phase separation. To the
organic layer was added aqueous sodium hydrogencarbonate solution,
and the mixture was subjected to phase separation. To the aqueous
layer was added aqueous hydrochloric acid solution for acidification,
to which ethyl acetate was added, and the mixture was subjected
to phase separation. The organic layer was washed with saturated
aqueous sodium chloride solution, dried over magnesium sulfate,
and then concentrated to give 0.183 g of 2-[2-{2-chloro-4-fluoro-
-5-[3-methyl-26-dioxo-4-(trifluoromethyl)-1236-tetra hydropyrimidin-1-yl]phenoxy}phenoxy]propionic
acid.
[0183] .sup.1H-NMR (CDCl.sub.3 250 MHz) .delta.(ppm): 1.53 (d,
3H, J=6.9 Hz), 3.51 (s, 3H), 4.76-4.83 (m, 1H), 6.32 (d, 1H, J=3.5
Hz), 6.63-6.67 (m, 1H), 7.0-7.1 (m, 2H), 7.1-7.2 (m, 2H), 7.38 (d,
1H, J=9.0 Hz).
[0184] Reference Production Example 3 38
[0185] First, 0.4 g of methyl. [2-{2-chloro-4-fluoro-5-[3-methyl-26-dioxo-
-4-(trifluoromethyl)-1236-tetrah ydropyrimidin-1-yl]phenoxy}phenoxy]ace-
tate was dissolved in 4 ml of 14-dioxane, to which a mixed solution
of 1 ml of concentrated hydrochloric acid and 1 ml of water was
added under stirring, and the mixture was heated and stirred under
reflux for 12 hours. The reaction mixture was then left for cooling,
into which ice water was poured, and after addition of ethyl acetate
and saturated aqueous sodium chloride solution, the mixture was
subjected to phase separation. To the organic layer was added aqueous
sodium hydrogencarbonate solution, and the mixture was subjected
to phase separation. To the aqueous layer was added aqueous hydrochloric
acid solution for acidification, to which ethyl acetate was added,
and the mixture was subjected to phase separation. The organic layer
was washed with saturated aqueous sodium chloride solution, dried
over magnesium sulfate, and then concentrated to give 0.252 g of
[2-{2-chloro-4-fluoro-5- -[3-methyl-26-dioxo-4-(trifluoromethyl)-1236-tetrah
ydropyrimidin-1-yl]phenoxy}phenoxy]acetic acid.
[0186] .sup.1H-NMR (CDCl.sub.3 250 MHz) .delta.(ppm): 3.50 (d,
3H, J=1.2 Hz), 4.66 (s, 2H), 6.31 (s, 1H), 6.69 (d, 1H, J=6.5 Hz),
6.98-7.20 (m, 4H), 7.38 (d, 1H, J=8.8 Hz).
[0187] Reference Production Example 4
[0188] Step 1: 39
[0189] First, 2.73 g of 2-methoxyphenol and 5.5 g of potassium
carbonate were added to 20 ml of N,N-dimethylformamide, and the
temperature was increased to 60.degree. C. To the mixture was added
dropwise a solution consisting of 4.3 g of N-(25-difluoro-4-nitrophenyl)acetamide
and 30 ml of N,N-dimethylformamide at a temperature of 60.degree.
C. to 65.degree. C. After stirring while keeping the temperature
for 1 hour, the mixture was cooled to room temperature and then
poured into water, and the mixture was extracted with ethyl acetate.
The organic layer was washed with diluted hydrochloric acid and
water, dried over magnesium sulfate, and then concentrated to give
5.52 g of N-[2-fluoro-5-(2-methoxyphenoxy)-- 4-nitrophenyl]acetamide.
[0190] .sup.1H-NMR (250 MHz, CDCl.sub.3) .delta.(ppm): 2.16 (3H,
s), 3.78 (3H, s), 6.85-7.22 (4H, m), 7.75-7.83 (1H, br), 7.83 (1H,
d, J=10.7 Hz), 8.04 (1H, d, J=6.9 Hz).
[0191] Step 2: 40
[0192] First, 5.4 g of N-[2-fluoro-5-(2-methoxyphenoxy)-4-nitrophenyl]acet-
amide was dissolved in 50 ml of methylene chloride, to which 4.7
g of boron tribromide was added under ice cooling. After stirring
at the same temperature for 2 hours, concentrated hydrochloric acid
was added, and the mixture was poured into water, and the mixture
was extracted with ethyl acetate. The organic layer was washed with
water, dried over magnesium sulfate, and then concentrated. The
resulting crystals were washed with t-butyl methyl ether to give
3.2 g of N-[2-fluoro-5-(2-hydrox- yphenoxy)-4-nitrophenyl]acetamide.
[0193] .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.(ppm): 2.20 (3H,
s), 6.33 (1H, bs), 6.86-7.23 (4H, m), 7.63 (1H, bs), 7.81 (1H, d,
J=10.3 Hz), 8.34 (1H, d, J=6.7 Hz).
[0194] Step 3: 41
[0195] First, 3.02 g of N-[2-fluoro-5-(2-hydroxyphenoxy)-4-nitrophenyl]ace-
tamide was dissolved in 20 ml of N,N-dimethylformamide, to which
1.5 g of potassium carbonate was added, and the mixture was stirred
at room temperature for 1 hour. Then, 1.6 g of methyl bromoacetate
was added at room temperature. After stirring at the same temperature
for 2 hours, the mixture was poured into water, and the mixture
was extracted with ethyl acetate. The organic layer was washed with
diluted hydrochloric acid and water, dried over magnesium sulfate,
and then concentrated. The resulting crystals were washed with t-butyl
methyl ether to give 3.01 g of methyl [2-(5-acetylamino-4-fluoro-2-nitrophenoxy)phenoxy]acetate.
[0196] .sup.1H-NMR (250 MHz, CDCl.sub.3) .delta.(ppm): 2.16 (3H,
s), 3.73 (3H, s), 4.62 (2H, s), 6.95-7.26 (4H, m), 7.71 (1H, bs),
7.85 (1H, d, J=10.7 Hz), 8.06 (1H, d, J=6.9 Hz).
[0197] Step 4: 42
[0198] To a mixture of 40 ml of acetic acid and 40 ml of water
was added 2.2 g of iron powder, and the temperature was increased
to 80.degree. C. To the mixture was added 3.0 g of methyl [2-(5-acetylamino-4-fluoro-2-nit-
rophenoxy)phenoxy]acetate, and the mixture was heated at reflux
for 30 minutes. The mixture was then poured into water, and the
mixture was extracted with ethyl acetate. The organic layer was
washed with water and saturated aqueous sodium bicarbonate solution,
dried over magnesium sulfate, and then concentrated to give 2.01
g of methyl [2-(5-acetylamino-2-amino-4-fluorophenoxy)phenoxy]acetate.
[0199] .sup.1H-NMR (250 MHz, CDCl.sub.3) .delta.(ppm): 2.11 (3H,
s), 3.31-4.15 (2H, br), 3.76 (3H, s), 4.71 (2H, s), 6.54 (1H, d,
J=11.9 Hz), 6.90-7.01 (4H, m), 7.17 (1H, bs), 7.69 (1H, d, J=7.5
Hz).
[0200] Step 5: 43
[0201] To 30 ml of concentrated hydrochloric acid was added 2.0
g of methyl [2-(5-acetylamino-2-amino-4-fluorophenoxy)phenoxy]acetate,
and the mixture was stirred at room temperature for 1 hour. Then,
an aqueous solution consisting of 0.42 g of sodium nitrite and 3
ml of water was added under ice cooling. After stirring at the same
temperature for 1 hour, 40 ml of t-butyl methyl ether was added
and 0.85 g of copper (I) chloride was added. After stirring for
30 minutes, water was added, and the mixture was extracted with
t-butyl methyl ether. The organic layer was washed with water, dried
over magnesium sulfate, and then concentrated. The residue was subjected
to column chromatography (eluent: hexane/ethyl acetate=2/1) to give
0.52 g of methyl [2-(5-acetylamino-2-chloro-4-fluorophenoxy)phenoxy]acetate.
[0202] m.p.: 138.9.degree. C.
[0203] Step 6: 44
[0204] To 10 ml of a methanol solution of a boron trifluoride methanol
complex was added 0.25 g of methyl [2-(5-acetylamino-2-chloro-4-fluorophe-
noxy)phenoxy]acetate, and the mixture was heated and stirred for
3 hours. The reaction mixture was then concentrated. The residue
was dissolved in ethyl acetate, and the solution was washed with
saturated aqueous sodium bicarbonate solution, dried over magnesium
sulfate, and then concentrated to give 0.2 g of methyl [2-(5-amino-2-chloro-4-fluorophenoxy)phenoxy]acet-
ate.
[0205] .sup.1H-NMR (250 MHz, CDCl.sub.3) .delta.(ppm): 3.74 (3H,
s), 3.86 (2H, br), 4.70 (2H, s), 6.36 (1H, d, J=8.21 Hz), 6.83-7.09
(5H, m).
[0206] Reference Production Example 5 45
[0207] First, 1.77 g of 245-trifluoronitrobenzene and 1.94 g
of 3-methyl-26-dioxo-4-(trifluoromethyl)-12 36-tetrahydropyrimidine
were dissolved in 10 ml of dimethylsulfoxide, to which 1.52 g of
anhydrous potassium carbonate was added at room temperature, and
the mixture was stirred at 80.degree. C. for 1 hour. The reaction
mixture was cooled to room temperature and then poured into ice
water, and the mixture was extracted with ethyl acetate. The organic
layer was washed with saturated aqueous sodium chloride solution,
dried over anhydrous magnesium sulfate, and then concentrated. The
residue was subjected to silica gel column chromatography to give
1.51 g of 25-difluoro-4-[3-methyl-26-dioxo-4-(tr- ifluoromethyl)-1236-tetrahydropyri
midin-1-yl]nitrobenzene.
[0208] m.p.: 150.degree. C.
[0209] Reference Production Example 6 46
[0210] A mixture of 15.16 g of methyl (2-hydroxyphenoxy)acetate,
29.23 g of 25-difluoro-4-[3-methyl-26-dioxo-4-(trifluoromethyl)-1236-tetrahy-
dropyri midin-1-yl]nitrobenzene, 11.5 g of anhydrous potassium carbonate,
and 160 ml of N,N-dimethylformamide was stirred at room temperature
for 30 minutes and then at 70.degree. C. for 3 hours. Another 5
g of methyl (2-hydroxyphenoxy)acetate was added, and the mixture
was stirred for 1 hour. The reaction mixture was poured into 2%
aqueous hydrochloric acid solution, and the mixture was extracted
with ethyl acetate. The organic layer was washed with saturated
aqueous sodium chloride solution, dried over anhydrous magnesium
sulfate, and then concentrated. The residue was subjected to silica
gel column chromatography to give 17.8 g of methyl [2-{4-fluoro-5-[3-methyl-26-dioxo-4-(trifluoromethyl)-1236-tetrahydro-
pyri midin-1-yl]-2-nitrophenoxy}phenoxy]acetate.
[0211] .sup.1H-NMR (CDCl.sub.3 300 MHz) .delta.(ppm): 3.50 (q,
3H, J=1.0 Hz), 3.70 (s, 3H), 4.63 (s, 2H), 6.28 (s, 1H), 6.88 (d,
1H, J=8.4 Hz), 6.93 (d, 1H, J=6.0 Hz), 7.0-7.1 (m, 1H), 7.1-7.3
(m, 2H), 7.87 (d, 1H, J=8.7 Hz).
[0212] Reference Production Example 7 47
[0213] To a mixture of 19 g of iron powder, 60 ml of acetic acid,
and 6 ml of water was added dropwise a solution of 19.12 g of methyl
[2-{4-fluoro-5-[3-methyl-26-dioxo-4-(trifluoromethyl)-1236-tetrahydro-
pyri midin-1-yl]-2-nitrophenoxy}phenoxy]acetate in 60 ml of acetic
acid under ice cooling. After completion of the dropwise addition,
the temperature was increased to room temperature, and the mixture
was stirred for 4 hours. The reaction mixture was filtered through
Celite, and the filtrate was diluted with ethyl acetate. The mixture
was washed with water, saturated aqueous sodium bicarbonate solution
and saturated aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate, and then concentrated. The residue was subjected
to silica gel chromatography to give 15.16 g of methyl [2-{2-amino-4-fluoro-5-[3-methyl-
-26-dioxo-4-(trifluoromethyl)-1236-tetrah ydropyrimidin-1-yl]phenoxy}p-
henoxy]acetate.
[0214] .sup.1H-NMR (CDCl.sub.3 250 MHz) .delta.(ppm): 3.51 (q,
3H, J=0.9 Hz), 3.76 (s, 3H), 4.2-4.4 (b, 2H), 4.69 (s, 2H), 6.29
(s, 1H), 6.6-6.7 (m, 2H), 6.9-7.1 (m, 4H).
[0215] Reference Production Example 8
[0216] Step 1: 48
[0217] A solution consisting of 4.85 g of methyl [2-(5-amino-2-chloro-4-fl-
uorophenoxy)phenoxy]acetate, 2.88 g of ethyl trifluoroacetoacetate,
and 40 ml of toluene was azeotropically distilled for 6 hours, while
passing through molecular sieves 5A to remove ethanol. The reaction
mixture was cooled, and 50 ml of ethyl acetate was then added. The
organic layer was washed with concentrated hydrochloric acid, water
and saturated aqueous sodium chloride solution, dried over anhydrous
sodium sulfate, and then concentrated under reduced pressure. The
residue was washed with hexane to give 5.82 g of crude methyl [2-(5-{33-dihydroxy-444-trifluorobutyry-
l}amino-2-chloro-4-fluorophenoxy)p henoxy]acetate.
[0218] m.p.: 165.3.degree. C.
[0219] Step 2: 49
[0220] To a solution of 1.0 g of crude methyl [2-(5-{33-dihydroxy-444-t-
rifluorobutyryl}amino-2-chloro-4-fluorophenoxy).sub.p henoxy]acetate
and 3 ml of tetrahydrofuran were added 4 ml of acetic acid and 0.87
g of potassium cyanate, and the mixture was stirred at room temperature
for 6 hours and then heated at reflux at 120.degree. C. for 2 hours.
After cooling, 30 ml of water was added, and the mixture was extracted
with ethyl acetate. The organic layer was washed with saturated
aqueous sodium bicarbonate solution, water and saturated aqueous
sodium chloride solution, dried over anhydrous sodium sulfate, and
then concentrated under reduced pressure. The residue was subjected
to silica gel column chromatography to give 0.67 g of methyl [2-{2-chloro-5-[26-dioxo-4-(trif-
luoromethyl)-1236-tetrahydropyrimidin-1-yl ]-4-fluorophenoxy}phenoxy]ac-
etate.
[0221] .sup.1H-NMR (CDCl.sub.3 250 MHz) .delta.(ppm): 3.72 (3H,
s), 4.65 (2H, s), 6.16 (1H, s), 6.77 (1H, d, J=6.6 Hz), 6.89-7.15
(4H, m), 7.36 (1H, d, J=8.9 Hz).
[0222] Reference Production Example 9
[0223] Step 1: 50
[0224] First, 2.08 g of potassium carbonate was added to a solution
of 3.0 g of 3-hydroxy-2-(methoxycarbonyl)methoxypyridine, 2.95 g
of N-(25-difluoro-4-nitrophenyl)acetamide, and 40 ml of N,N-dimethylformamide.
The mixture was stirred at 60.degree. C. to 70.degree. C. for 2
hours, cooled to room temperature, and then poured into water. The
mixture was extracted with ethyl acetate. The organic layer was
washed with saturated aqueous sodium chloride solution, dried over
anhydrous magnesium sulfate, and then concentrated to give crude
crystals. The crude crystals were washed with diisopropyl ether
to give 3.67 g of N-[2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}-4-nitro-
phenyl]acet amide.
[0225] .sup.1H-NMR (CDCl.sub.3 250 MHz) .delta.(ppm): 2.21 (s,
3H), 3.72 (s, 3H), 4.90 (s, 2H), 6.96 (dd, 1H, J=7.8 5.0 Hz), 7.35
(dd, 1H, J=7.8 1.6 Hz), 7.5-7.6 (b, 1H), 7.90 (d, 1H, J=10.6 Hz),
7.97 (dd, 1H, J=5.0 1.6 Hz), 8.15 (d, 1H, J=6.8 Hz).
[0226] Step 2: 51
[0227] To a mixture of 3.6 g of iron powder, 10 ml of acetic acid,
and 1 ml of water was added dropwise a solution of 3.67 g of N-[2-fluoro-5-{2-(methoxycarbonyl)methoxy}-3-pyridyloxy]-4-nitrophenyl]ac-
e tamide, 12 ml of acetic acid, and 2 ml of ethyl acetate, while
the temperature of the reaction mixture was kept at 45.degree. C.
or lower. After completion of the dropwise addition, the reaction
mixture was stirred at 40.degree. C. for 1 hour. The reaction mixture
was then filtered through Celite, and the filtrate was concentrated.
The residue was diluted with saturated aqueous sodium bicarbonate
solution, and the mixture was extracted with ethyl acetate. The
organic layer was washed with saturated aqueous sodium bicarbonate
solution, dried over anhydrous magnesium sulfate, and then concentrated.
The residue was washed with diisopropyl ether to give 3.09 g of
N-[4-amino-2-fluoro-5-{2-(methoxycarb- onyl)methoxy-3-pyridyloxy}phenyl]ac
etamide.
[0228] .sup.1H-NMR(CDCl.sub.3 250 MHz) .delta.(ppm): 2.15 (s,
3H), 3.77 (s, 3H), 3.9-4.1 (b, 2H), 5.03 (s, 2H), 6.56 (d, 1H, J=11.8
Hz), 6.84 (dd, 1H, J=7.9 5.0 Hz), 7.0-7.2 (b, 1H), 7.14 (dd, 1H,
J=7.9 1.5 Hz), 7.80 (dd, 1H, J=5.0 1.5 Hz), 7.84 (d, 1H, J=7.6
Hz).
[0229] Step 3: 52
[0230] A solution of 2.01 g of isoamyl nitrite in 1 ml of acetonitrile
was added dropwise to a mixture of 2.0 g of N-[4-amino-2-fluoro-5-{2-(methoxy-
carbonyl)methoxy-3-pyridyloxy}phenyl]ac etamide, 1.13 g of copper
(I) chloride, 2.31 g of copper (II) chloride, and 20 ml of acetonitrile
at room temperature, and the mixture was stirred for 1 hour. The
reaction mixture was poured into 2% hydrochloric acid, and the mixture
was extracted with ethyl acetate. The organic layer was washed with
saturated aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate, and then concentrated. The residue was subjected
to silica gel column chromatography to give 1.04 g of N-[4-chloro-2-fluoro-5-{2-(methoxycarbon-
yl)methoxy-3-pyridyloxy}phenyl]ac etamide.
[0231] .sup.1H-NMR (CDCl.sub.3 250 MHz) .delta.(ppm): 2.18 (s,
3H), 3.75 (s, 3H), 4.98 (s, 2H), 6.87 (dd, 1H, J=7.8 4.9 Hz), 7.08
(dd, 1H, J=7.8 1.4 Hz), 7.23 (d, 1H, J=10.3 Hz), 7.3-7.4 (b, 1H),
7.86 (dd, 1H, J=4.9 1.4 Hz) 8.07 (d, 1H, J=7.3 Hz).
[0232] Step 4: 53
[0233] First, 20 ml of a methanol solution of a boron trifluoride
methanol complex was mixed with 1.04 g of N-[4-chloro-2-fluoro-5-{2-(methoxycarbon-
yl)methoxy-3-pyridyloxy}phenyl]ac etamide, and the mixture was stirred
at 60.degree. C. to 70.degree. C. for 3 hours and then concentrated.
The residue was diluted with saturated aqueous sodium bicarbonate
solution, and the mixture was extracted with ethyl acetate. The
organic layer was washed with saturated aqueous sodium chloride
solution, dried over anhydrous magnesium sulfate, and then concentrated.
The residue was subjected to column chromatography to give 0.87
g of 4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}aniline.
[0234] .sup.1H-NMR (CDCl.sub.3 250 MHz) .delta.(ppm) 3.77 (s,
3H), 3.7-3.9 (b, 2H), 5.00 (s, 2H), 6.49 (d, 1H, J=8.2 Hz), 6.88
(dd, 1H, J=7.9 5.0 Hz), 7.08 (d, 1H, J=10.3 Hz), 7.10 (dd, 1H,
J=7.9 1.6 Hz), 7.87 (dd, 1H, J=5.0 1.6 Hz).
[0235] Step 5: 54
[0236] A mixture of 0.5 g of 4-chloro-2-fluoro-5-{2-(methoxycarbonyl)metho-
xy-3-pyridyloxy}aniline, 0.28 g of ethyl trifluoroacetoacetate,
and 10 ml of toluene was azeotropically distilled for 3 hours, while
passing through molecular sieves 5A to remove ethanol. After cooling,
the reaction mixture was concentrated to give 0.71 g of N-[4-chloro-2-fluoro-5-{2-(methoxycarbonyl)methoxy-3-pyridyloxy}phenyl]tr-
i fluoroacetoacetamide.
[0237] m.p.: 158.8.degree. C.
[0238] Step 6: 55
[0239] To a mixture of 0.71 g of N-[4-chloro-2-fluoro-5-{2-(methoxycarbony-
l)methoxy-3-pyridyloxy}phenyl]tri fluoroacetoacetamide and 2 ml
of acetic acid was added sodium cyanate, and the mixture was stirred
at 50.degree. C. for 1 hour and then at 110.degree. C. for 1.5 hours.
After cooling, water was poured into the reaction mixture, and the
mixture was extracted with ethyl acetate. The organic layer was
washed with saturated aqueous sodium bicarbonate solution, saturated
aqueous sodium chloride solution, dried over anhydrous magnesium
sulfate, and then concentrated. The residue was subjected to silica
gel column chromatography to give 0.30 g of 3-{2-chloro-4-fluoro-5-[26-dioxo-4-(trifluoromethyl)-1236-tetrahyd-
ropyridi n-1-yl]phenoxy}-2-(methoxycarbonyl) methoxypyridine.
[0240] .sup.1H-NMR (CDCl.sub.3 250 MHz) .delta.(ppm): 3.70 (s,
3H), 4.93 (s, 2/2H), 4.94 (s, 2/2H), 6.19(s, 1H), 6.9-7.0 (m, 2H),
7.3-7.4 (m, 1H), 7.38 (d, 1H, J=8.9 Hz), 7.93 (dd, 1H, J=4.9 1.6
Hz);
[0241] m.p.: 75.3.degree. C.
[0242] Reference Production Example 10
[0243] Step 1: 56
[0244] First, 0.4 g of sodium hydride was added to a mixture of
1.59 g of 2-chloro-3-nitropyridine, 0.95 g of methyl glycolate,
and 10 ml of 14-dioxane at 10.degree. C. After stirring at room
temperature for 2 hours, the reaction mixture was poured into ice
water, and the mixture was extracted with ethyl acetate. The organic
layer was dried over anhydrous magnesium sulfate and then concentrated.
The residue was subjected to silica gel column chromatography to
give 1.5 g of 2-(methoxycarbonyl)methoxy-3-nitropyridine.
[0245] m.p.: 61.5.degree. C.
[0246] Step 2: 57
[0247] A mixture of 0.3 g of 2-(methoxycarbonyl)methoxy-3-nitropyridine,
20 mg of platinum oxide, and 1.4 ml of ethanol was stirred at room
temperature under an atmosphere of hydrogen gas for 3 hours. The
gas in the atmosphere on the reaction system was replaced with nitrogen
gas, and the reaction mixture was filtered through Celite. The filtrate
was concentrated. The residue was subjected to silica gel column
chromatography to give 0.22 g of 3-amino-2-(methoxycarbonyl)methoxypyridi-
ne.
[0248] .sup.1H-NMR(CDCl.sub.3 250 MHz) .delta.(ppm): 3.77 (s,
3H), 3.85 (bs, 2H), 4.95 (s, 2H), 6.75 (dd, 1H, J=7.5 5.0 Hz),
6.91 (dd, 1H, J=7.5 1.6 Hz), 7.50 (dd, 1H, J=5.0 1.6 Hz).
[0249] Step 3: 58
[0250] First, 1.6 g of a boron trifluoride diethyl ether complex
was added dropwise to a mixture of 1.0 g of 3-amino-2-(methoxycarbonyl)methoxypyrid-
ine, 3 (ml of 12-dimethoxyethane, and 1 ml of dichloromethane at
-10.degree. C. After stirring at the same temperature for 10 minutes,
a solution of 0.68 g of t-butyl nitrite in 1 ml of 12-dimethoxyethane
was added dropwise to the reaction mixture at -5.degree. C. or lower.
After stirring at the same temperature for 30 minutes, n-pentane
was poured into the mixture. The lower one of the two layers separated
was dissolved in 5 ml of acetic anhydride, and the solution was
stirred at 80.degree. C. for 1 hour. After the solvent was distilled
out, the residue was subjected to silica gel chromatography to give
0.45 g of 3-acetoxy-2-(methoxycarbonyl)methoxypyridine.
[0251] .sup.1H-NMR (CDCl.sub.3 250 MHz) .delta.(ppm): 2.33 (s,
3H), 3.75 (s, 3H), 4.92 (s, 2H), 6.93 (dd, 1H, J=7.7 5.0 Hz), 7.38
(dd, 1H, J=7.7 1.6 Hz), 7.97 (dd, 1H, J=5.0 1.6 Hz).
[0252] Step 4: 59
[0253] A mixture of 0.1 g of 3-acetoxy-2-(methoxycarbonyl)methoxypyridine,
31 mg of potassium carbonate, and 1 ml of methanol was stirred at
room temperature for 3 hours. The reaction mixture was poured into
water, and the mixture was extracted with ethyl acetate. The organic
layer was dried over anhydrous magnesium sulfate and then concentrated.
The residue was subjected to silica gel column chromatography to
give 73 mg of 3-hydroxy-2-(methoxycarbonyl)methoxypyridine.
[0254] .sup.1H-NMR (CDCl.sub.3 250 MHz) .delta.(ppm): 3.78 (s,
3H), 4.98 (s, 2H), 6.84 (dd, 1H, J=7.7 5.0 Hz), 7.17 (dd, 1H, J=7.7
1.3 Hz), 7.63 (dd, 1H, J=5.0 1.3 Hz).
[0255] Step 5: 60
[0256] To a mixture of 0.29 g of 3-hydroxy-2-(methoxycarbonyl)methoxypyrid-
ine, 0.23 g of 25-difluoro-4-[3-methyl-26-dioxo-4-(trifluoromethyl)-12-
36-tetrahydropyri midin-1-yl]nitrobenzene, and 3.2 ml of N,N-dimethylformamide
was added 0.11 g of potassium carbonate, and the mixture was stirred
at 70.degree. C. for 2 hours. Another 0.12 g of 25-difluoro-4-[3-methyl-26-dioxo-4-(trifluoromethyl)-1236-tetrahydro-
pyri midin-1-yl]nitrobenzene and another 0.05 g of potassium carbonate
were added, and the mixture was stirred at 70.degree. C. for 1 hour.
The reaction mixture was cooled to room temperature and then poured
into ice water, and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated aqueous sodium chloride
solution, dried over anhydrous magnesium sulfate, and then concentrated.
The residue was subjected to silica gel column chromatography to
give 0.39 g of 3-{4-fluoro-5-[3-methyl-26-dioxo-4-(trifluoromethyl)-1236-tetrahydrop-
yrim idin-1-yl]-2-nitrophenoxy}-2-(methoxycarbonyl)methoxypyridine.
[0257] .sup.1H-NMR (CDCl.sub.3 250 MHz) .delta.(ppm): 3.51 (q,
3H, J=1.1 Hz), 3.68 (s, 3H), 4.86 (d, 1H), 4.98 (d, 1H), 6.29 (s,
1H), 6.99 (dd, 1H, J=7.8 4.9 Hz), 7.11 (d, 1H, J=6.0 Hz), 7.51
(dd, 1H, J=7.8 1.6 Hz), 7.87 (d, 1H, J=8.6 Hz), 7.99 (dd, 1H, J=4.9
1.6 Hz).
[0258] Step 6: 61
[0259] To a mixture of 0.3 g of iron powder, 3 ml of acetic acid,
and 0.3 ml of water was added dropwise a solution of 0.30 g of 3-{4-fluoro-5-[3-methyl-26-dioxo-4-(trifluoromethyl)-1236-tetrahydrop-
yrim idin-1-yl]-2-nitrophenoxy}-2-(methoxycarbonyl)methoxypyridine
in 2 ml of acetic acid, while the temperature of the reaction mixture
was kept at 35.degree. C. or lower. After completion of the dropwise
addition, the mixture was stirred for 2 hours and then filtered
through Celite. The filtrate was diluted with ethyl acetate, and
the mixture was neutralized with saturated aqueous sodium bicarbonate
solution. The organic layer was washed with saturated aqueous sodium
chloride solution, dried over anhydrous magnesium sulfate, and then
concentrated. The residue was subjected to silica gel column chromatography
to give 0.24 g of 3-{2-amino-4-fluoro-5-[3-methyl-26-dioxo-4-(trifluoromethyl)-1236-tet-
rahy dropyrimidin-1-yl]phenoxy}-2-(methoxycarbonyl)methoxypyridine.
[0260] .sup.1H-NMR (CDCl.sub.3 250 MHz) .delta.(ppm): 3.52 (s,
3H), 3.74 (s, 3H), 4.29 (bs, 2H), 5.00 (S, 2H), 6.30 (s, 1H), 6.61
(d, 1H, J=11.3 Hz), 6.76 (d, 1H, J=6.8 Hz), 6.86 (dd, 1H, J=7.8
5.0 Hz), 7.22 (dd, 1H, J=7.8 1.1 Hz), 7.82 (dd, 1H, J=5.0 1.1
Hz).
[0261] Reference Production Example 11
[0262] Step 1:
[0263] First, 0.8 g of sodium hydride was added to a mixture of
3.17 g of 2-chloro-3-nitropyridine, 2.19 g of methyl lactate, and
20 ml of 14-dioxane at 10.degree. C., and the mixture was stirred
at room temperature for 1.5 hours. The reaction mixture was poured
into ice water, and the mixture was extracted with ethyl acetate.
The organic layer was dried over anhydrous magnesium sulfate and
then concentrated. The residue was subjected to silica gel column
chromatography to give 3.3 g of 2-{1-(methoxycarbonyl)ethoxy}-3-nitropyridine.
[0264] .sup.1H-NMR (CDCl.sub.3 300 MHz) .delta.(ppm): 1.70 (d,
3H, J=7.0 Hz), 3.74 (s, 3H), 5.46 (q, 1H, J=7.0 Hz), 7.07 (dd, 1H,
J=7.8 5.0 Hz), 8.2-8.4 (m, 2H).
[0265] Step 2:
[0266] A mixture of 1.7 g of 2-{1-(methoxycarbonyl)ethoxy}-3-nitropyridine-
, 102 mg of platinum oxide, and 7.5 ml of ethanol was stirred at
room temperature under an atmosphere of hydrogen gas for 3.5 hours.
The gas in the atmosphere on the reaction system was replaced with
nitrogen gas, and the reaction mixture was filtered through Celite.
The filtrate was concentrated. The residue was subjected to silica
gel column chromatography to give 1.16 g of 3-amino-2-{1-(methoxycarbonyl)ethoxy}pyr-
idine.
[0267] .sup.1H-NMR (CDCl.sub.3 300 MHz) .delta.(ppm): 1.63 (d,
3H, J=6.8 Hz), 3.74 (s, 3H), 3.84 (bs, 2H), 5.38 (d, 1H, J=6.8 Hz),
6.72 (dd, 1H, J=7.7 5.0 Hz), 6.90 (dd, 1H, J=7.7 1.4 Hz), 7.48
(dd, 1H, J=5.0 1.4 Hz).
[0268] Step 3:
[0269] First, 1.5 ml of a boron trifluoride diethyl ether complex
was added dropwise to a mixture of 1.1 g of 3-amino-2-{1-(methoxycarbonyl)eth-
oxy}pyridine, 1 ml of 12-dimethoxyethane, and 1 ml of dichloroethane
at -10.degree. C. After stirring at the same temperature for 10
minutes, a solution of 0.8 ml of t-butyl nitrite in 1 ml of 12-dimethoxyethane
was added dropwise to the reaction mixture at -5.degree. C. or lower.
After stirring at the same temperature for 30 minutes, n-pentane
was poured into the mixture. The lower one of the two layers separated
was dissolved in acetic anhydride, and the solution was stirred
at 70.degree. C. for 1 hour. After the solvent was distilled out,
the residue was subjected to silica gel chromatography to give 0.34
g of 3-acetoxy-2-{1-(methoxycarbon- yl)ethoxy}pyridine.
[0270] .sup.1H-NMR (CDCl.sub.3 300 MHz) .delta.(ppm): 1.60 (d,
1H, J=7.0 Hz), 2.33 (s, 3H), 3.73 (s, 3H), 5.34 (q, 1H, J=7.0 Hz),
6.91 (dd, 1H, J=7.6 5.0 Hz), 7.36 (dd, 1H, J=7.6 1.5 Hz), 7.97
(dd, 1H, J=5.0 1.5 Hz).
[0271] Step 4:
[0272] A mixture of 0.34 g of 3-acetoxy-2-{1-(methoxycarbonyl)ethoxy}pyrid-
ine, 0.11 g of potassium carbonate, and 2 ml of methanol was stirred
at room temperature for 1 hour. The reaction mixture was poured
into water, and the mixture was extracted with ethyl acetate. The
organic layer was dried over anhydrous magnesium sulfate and then
concentrated. The residue was subjected to silica gel column chromatography
to give 198 mg of 3-hydroxy-2-{1-(methoxycarbonyl)ethoxy}pyridine.
[0273] .sup.1H-NMR (CDCl.sub.3 300 MHz) .delta.(ppm): 1.64 (d,
1H, J=7.0 Hz), 3.75 (s, 3H), 5.45 (q, 1H, J=7.0 Hz), 6.0-6.2 (bs,
1H), 6.83 (dd, 1H, J=7.7 5.0 Hz), 7.15 (dd, 1H, J=7.7 1.5 Hz),
7.63 (dd, 1H, J=5.0 1.5 Hz).
[0274] Step 5:
[0275] To a mixture of 0.18 g of 3-hydroxy-2-{1-(methoxycarbonyl)ethoxy}py-
ridine, 0.19 g of 25-difluoro-4-[3-methyl-26-dioxo-4-(trifluoromethyl)-1-
,236-tetrahydropyri midin-1-yl]nitrobenzene, and 2.0 ml of N,N-dimethylformamide
was added 90 mg of potassium carbonate, and the mixture was stirred
at 70.degree. C. for 3 hours. The reaction mixture was cooled to
room temperature and then poured into ice water, and the mixture
was extracted with ethyl acetate. The organic layer was washed with
saturated aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate, and then concentrated. The residue was subjected
to silica gel column chromatography to give 0.21 g of 3-{4-fluoro-5-[3-methyl-26-dioxo-4-(trifluoromethyl)-1236-tetrahydrop-
yrim idin-1-yl]-2-nitrophenoxy}-2-{1-(methoxycarbonyl)ethoxy}pyridine
as a mixture of diastereoisomers.
[0276] .sup.1H-NMR (CDCl.sub.3 300 MHz) .delta.(ppm): 1.45 (d,
3/2H, J=7.1 Hz), 1.46 (d, 3/2H, J=7.1 Hz), 3.49 (s, 3/2H), 3.51
(s, 3/2H), 3.66 (s, 3H), 5.29 (q, 1/2H, J=7.1 Hz), 5.31 (q, 1/2H,
J=7.1 Hz), 6.28 (s, 1/2H), 6.30 (s, 1/2H), 6.9-7.0 (m, 1H), 7.10
(d, 1/2H, J=6.1 Hz), 7.17 (d, 1/2H, J=6.1 Hz), 7.4-7.6 (m, 1H),
7.8-7.9 (m, 1H), 7.9-8.0 (m, 1H).
[0277] Step 6:
[0278] To a mixture of 0.21 g of iron powder, 3 ml of acetic acid,
and 0.3 ml of water was added dropwise a solution of 3-{4-fluoro-5-[3-methyl-26--
dioxo-4-(trifluoromethyl)-1236-tetrahydropyrim idin-1-yl]-2-nitrophenox-
y}-2-{1-(methoxycarbonyl)ethoxy}pyridine in 1.2 ml of acetic acid,
while the temperature of the reaction mixture was kept at 35.degree.
C. or lower. After completion of the dropwise addition, the mixture
was stirred for 1 hour and then filtered through Celite. The filtrate
was diluted with ethyl acetate. The mixture was neutralized with
saturated aqueous sodium bicarbonate solution. The organic layer
was washed with saturated aqueous sodium chloride solution, dried
over anhydrous magnesium sulfate, and then concentrated. The residue
was subjected to silica gel chromatography to give 0.16 g of 3-{2-amino-4-fluoro-5-[3-methyl-26-diox-
o-4-(trifluoromethyl)-1236-tetrahy dropyrimidin-1-yl]phenoxy}-2-{1-(met-
hoxycarbonyl)ethoxy}pyridine as a mixture of diastereoisomers.
[0279] .sup.1H-NMR (CDCl.sub.3 300 MHz) .delta.(ppm): 1.61 (d,
3H, J=7.1 Hz), 3.52 (s, 3H), 3.72 (s, 3H), 4.28 (bs, 2H), 5.40 (q,
1/2H, J=7.1 Hz), 5.41 (q, 1/2H, J=7.1 Hz), 6.30 (s, 1H), 6.62 (d,
1H, J=10.9 Hz), 6.7-6.8 (m, 1H), 6.8-6.9 (m, 1H), 7.2-7.3 (m, 1H),
7.7-7.9 (m, 1H).
[0280] Reference Production Example 12
[0281] Step 1: 62
[0282] First, 0.8 g of sodium hydride was added to a mixture of
3.17 g of 2-chloro-3-nitropyridine, 2.12 g of methyl thioglycolate,
and 20 ml of tetrahydrofuran at 0.degree. C. After stirring at room
temperature for 2 hours, the reaction mixture was poured into ice
water, and the mixture was extracted with ethyl acetate. The organic
layer was dried over anhydrous magnesium sulfate and then concentrated.
The residue was washed with diisopropyl ether and hexane to give
3.1 g of 2-(methoxycarbonyl)methylthio-3-nitropyridine.
[0283] .sup.1H-NMR (CDCl.sub.3 300 MHz) .delta.(ppm): 3.75 (s,
3H), 3.98 (s, 2H), 7.24 (dd, 1H, J=8.0 4.8 Hz), 8.54 (dd, 1H, J=8.0
1.8 Hz), 8.66 (dd, 1H, J=4.8 1.8 Hz).
[0284] Step 2: 63
[0285] A mixture of 3.0 g of 2-(methoxycarbonyl)methylthio-3-nitropyridine-
, 180 mg of platinum oxide, and 14 ml of ethanol was stirred at
room temperature under an atmosphere of hydrogen gas for 3 hours.
The gas in the atmosphere on the reaction system was placed with
nitrogen gas, and the reaction mixture was filtered through Celite.
The filtrate was concentrated. The residue was subjected to silica
gel column chromatography to give 2.54 g of 3-amino-2-(methoxycarbonyl)methylthiopyr-
idine.
[0286] .sup.1H-NMR (CDCl.sub.3 250 MHz) .delta.(ppm): 3.73 (s,
3H), 4.03 (s, 2H), 6.2-6.4 (b, 1H), 7.06 (dd, 1H, J=8.0 4.9 Hz),
7.1-7.2 (bs, 1H), 7.47 (dd, 1H, J=8.0 1.4 Hz), 8.05 (dd, 1H, J=4.9
1.4 Hz).
[0287] Step 3: 64
[0288] First, 1.92 g of trifluoromethanesulfonic acid was added
dropwise to a mixture of 2.54 g of 3-amino-2-(methoxycarbonyl)methylthiopyridine,
6 ml of 12-dimethoxyethane, and 2 ml of dichloromethane at -10.degree.
C. After stirring at the same temperature for 10 minutes, a solution
of 1.59 g of t-butyl nitrite in 1 ml of 12-dimethoxyethane was
added dropwise to the reaction mixture at -5.degree. C. or lower.
After stirring at the same temperature for 30 minutes, n-pentane
was poured into the mixture. The lower one of the two layers separated
was dissolved in 3 ml of acetic anhydride, and the solution was
stirred at 50.degree. C. to 70.degree. C. for 1 hour. The reaction
mixture was cooled to room temperature and then poured into water,
and the mixture was extracted with t-butyl methyl ether. The organic
layer was washed with saturated aqueous sodium hydrogencarbonate
solution and saturated aqueous sodium chloride solution, dried over
anhydrous magnesium sulfate, and then concentrated. The residue
was subjected to silica gel chromatography to give 0.48 g of 3-acetoxy-2-(methoxycarbonyl)methylthiopyridine.
[0289] .sup.1H-NMR (CDCl.sub.3 250 MHz) .delta.(ppm): 2.36 (s,
3H), 3.74 (s, 3H), 4.00 (s, 2H), 7.07 (dd, 1H, J=8.0 4.7 Hz), 7.37
(dd, 1H, J=8.0 1.5 Hz), 8.29 (dd, 1H, J=4.7 1.5 Hz).
[0290] Step 4: 65
[0291] A mixture of 0.48 g of 3-acetoxy-2-(methoxycarbonyl)methylthiopyrid-
ine, 0.15 g of potassium carbonate, and 3 ml of methanol was stirred
at room temperature for 3 hours. The reaction mixture was poured
into water, and the mixture was extracted with ethyl acetate. The
organic layer was dried over anhydrous magnesium sulfate and then
concentrated. The residue was subjected to silica gel column chromatography
to give 0.26 g of 3-hydroxy-2-(methoxycarbonyl)methylthiopyridine.
[0292] .sup.1H-NMR (CDCl.sub.3 250 MHz) .delta.(ppm): 3.74 (s,
3H), 3.92 (s, 2H), 7.02 (dd, 1H, J=8.1 4.6 Hz), 7.13 (d, 1H, J=8.1
Hz), 8.06 (d, 1H, J=4.6 Hz).
[0293] Step 5: 66
[0294] To a mixture of 0.26 g of 3-hydroxy-2-(methoxycarbonyl)methylthiopy-
ridine, 0.38 g of 25-difluoro-4-[3-methyl-26-dioxo-4-(trifluoromethyl)-1-
,236-tetrahydropyri midin-1-yl]nitrobenzene, and 2 ml of N,N-dimethylformamide
was added 0.17 g of potassium carbonate, and the mixture was stirred
at 70.degree. C. for 2 hours. The reaction mixture was cooled to
room temperature and then poured into ice water, and the mixture
was extracted with ethyl acetate. The organic layer was washed with
saturated aqueous sodium chloride solution, dried over anhydrous
magnesium sulfate, and then concentrated. The residue was subjected
to silica gel column chromatography to give 0.49 g of 3-{4-fluoro-5-[3-methyl-26-dioxo-4-(trifluoromethyl)-1236-tetrahydrop-
yrim idin-1-yl]-2-nitrophenoxy}-2-(methoxycarbonyl)methylthiopyridine.
[0295] .sup.1H-NMR (CDCl.sub.3 300 MHz) .delta.(ppm): 3.54 (s,
3H), 3.73 (s, 3H), 4.01 (s, 2H), 6.33 (s, 1H), 7.0-7.1 (m, 2H),
7.18 (dd, 1H, J=7.8 1.3 Hz), 7.92 (d, 1H, J=8.5 Hz), 8.28 (dd,
1H, J=4.4 1.3 Hz).
[0302] The following will describe formulation examples. In these
formulation examples, "parts" represents parts by weight.
Formulation Example 1
[0303] Fifty parts of each of compounds a-1 to a-124 compounds
b-1 to b-124 and compounds c-1 to c-48 3 parts of calcium lignin
sulfonate, 2 parts of sodium lauryl sulfate, and 45 parts of synthetic
hydrated silicon oxide are well pulverized and mixed to give a wettable
powder for each compound.
Formulation Example 2
[0304] Seventy parts of each of compounds a-1 to a-124 compounds
b-1 to b-124 and compounds c-1 to c-48 3 parts of calcium lignin
sulfonate, 2 parts of sodium lauryl sulfate, and 25 parts of synthetic
hydrated silicon oxide are well pulverized and mixed to give a wettable
powder for each compound.
Formulation Example 3
[0305] Twenty parts of each of compounds a-1 to a-124 compounds
b-1 to b-124 and compounds c-1 to c-48 3 parts of polyoxyethylene
sorbitan monooleate, 3 parts of CMC (carboxymethylcellulose), and
74 parts of water are mixed and wet pulverized so that the mean
particle size comes to 5 .mu.m or smaller to give a flowable of
each compound.
Formulation Example 4
[0306] Forty parts of each of compounds a-1 to a-124 compounds
b-1 to b-124 and compounds c-1 to c-48 3 parts of polyoxyethylene
sorbitan monooleate, 3 parts of CMC (carboxymethylcellulose), and
54 parts of water are mixed and wet pulverized so that the mean
particle size comes to 5 .mu.m or smaller to give a flowable of
each compound.
[0307] The following will describe test example and the present
invention should not be limited to the test example.
[0308] Test Example
[0309] Seed potatoes were planted on a field and grown. At the
time of the foliage turning yellow, 2.5 parts of each of compounds
a-5 and a-6 10 parts of Sorpol 3890 (Toho Chemical Industry Co.,
Ltd.), and 87.5 parts of SOLVESSO 200 (Exxon Mobile Chemical Company)
were well mixed to give an emulsifiable concentrate for each compound,
diluted at a prescribed dose with water containing 1% (v/v) crop
oil concentrate (COC), and the dilution was uniformly sprayed to
the plants. One section of the treated field are 2.1.times.15.2
m in area, and the potato plants on 14 day after the treatment were
examined for the desiccant effect. The results are shown in Table
4. In the table, the desiccation effect was evaluated with following
criteria.
[0310] Evaluating criteria
[0311] 1: The desiccated area of foliage is 0 to 29%
[0312] 2: The desiccated area of foliage is 30 to 69%
[0313] 3: The desiccated area of foliage is 70 to 89%
[0314] 4: The desiccated area of foliage is 90 to 99%
[0315] 5: The desiccated area of foliage is 100%
[0316] The treatment was done in 3 sections, the result was indicated
with an average of the 3 sections.
4 TABLE 4 Application amount Desiccation Test compound (g/ha) effect
Compound a-5 10 5 Compound a-6 10 5
INDUSTRIAL APPLICABILITY
[0317] The use of the present desiccant on a suitable time prior
to harvest can gain the plants whose aboveground parts is sufficiently
desiccated on the harvest time, so that works on and/or after the
harvest can easily be performed. |