JPH0447667B2 - - Google Patents

Description

[Detailed description of the invention] (Industrial application field) The present invention has a wide range of activity as a herbicide.
A new type of 2,6-substituted-3,5-pyridine
dicarboxylic acid derivatives. (Issues to be solved by prior art and inventions)
title) Pyridine derivatives have been used in biological sciences for many years.
Its use has been studied. For example, 2,
6-bis-(trifluoromethyl)-4-pyridino
as disclosed in U.S. Pat. No. 3,748,334.
Sea urchins are useful as herbicides and fungicides.
was found. Such compounds are hydroxyl radicals
Characterized by substitution at the 4-position by Cal. Hi
In addition to the droxy radical, the pyridine nucleus also acts as a block.
Substitution with mono, chloro or iodoradicals is also possible.
Wear. Trifluoromethylpyridine derivatives are available in the U.S.
Also disclosed in Patent Nos. 2516402 and 3705170
There, the nucleus contains not only halogens but also many
Further substituted with other substituents. these
Some of the compounds are useful as herbicides
This is also attracting attention. Also, -4 position is alkyl, phenyl, naphthyl or
or 4-substituted with a pyridyl group
2,6-dichloro-3,5-dicyanopyridine is
It is known for its fungicidal activity. Such a compound
Although the product is disclosed in U.S. Pat. No. 3,284,293,
On the other hand, a similar compound was disclosed in US Patent No. 3,629,270.
where the heteroatom is oxygen or sulfur.
The 4-position is substituted with a heterocyclic group. EPO Patent No. 44262 states that
2,6-dialkyl-3-phenylcarbamyl-
5-pyridinecarboxylate and -5-sia
No-compounds are disclosed. 4- of the pyridine ring
2-haloalkyl radicals and other
No substitutions disclosed. These pyridine derivatives are also being tested for new herbicides.
Received attention for search and U.S. Patent No. 1944412
No. 3637716 and No. 3651070.
Ta. All of these patents cover dicarboxypyridine
discloses polyhalo derivatives of everything is a circle
by halogens in the 3- and 5-positions on the carbon.
have direct substitution in common; on the other hand, 2-
and the 6-position is occupied by a carboxylate group.
It is. 4-position is halogen, hydroxyl radical
including carboxylic, alkoxy, and carboxyl groups.
open for replacement by a wide range of substances
Ru. Such compounds are herbicides, fungicides and fungicides.
found its use as a drug. The 4th position is based on silver salt.
U.S. Patent No. 1944412
X by silent injection of such a compound.
It is disclosed that the method was used to generate line images. (Means for solving problems) Proposal of a weed control method using the novel pyridines of the present invention
It is an object of the present invention to provide this information. Another object of the invention is the preparation of the novel compounds of the invention.
and new manufacturing methods for useful intermediates.
It is to provide. The novel compounds of the invention can be used as herbicides or
is useful as an intermediate for providing an agent, and
formula, [In the formula, R is lower alkyl, lower alkenyl, lower
alkynyl, lower alkenylalkyl, haloar
lukyl, haloalkenyl, C_3-7cycloalkyl,
C_3-6cycloalkanylalkyl, aryl, ant
methyl, alkoxyalkyl, benzyloxy
dimethyl, alkylthioalkyl, dialkoxy
Alkyl, (1-alkoxy-1-alkylthio)
Alkyl, aminoalkyl, alkylaminoal
Kyl, dialkylaminoalkyl, alkylsul
Honyl alkyl, alkylsulfinyl alkyl
substituted by a dialkyl sulfonium salt
Alkyl, cyanoalkyl, carbamyl alkyl
carbalkoxyalkyl, carbalkoxyalkyl, carbalkoxyalkyl
Sialkenyl, formalylalkyl, dialkyl
aminoalkenyl, and furyl, pyridyl, and
enyl, thiiranil, oxiranil and aziry
saturated and unsaturated selected from the group consisting of dinyls;
It is a heterocyclic group, and the group has a pyridine group formed by a C-C bond.
attached to the ring, and furyl, pyridine
ru, thienyl, thiiranyl, oxiranil and
saturated and selected from the group consisting of aziridinyl
Lower alkyl substituted with an unsaturated heterocyclic group
selected from the group consisting of; and methyl fluoride,
However, R₁and R₂One of them is methyl fluoride
and X and Y are {In the formula, Z₁is O and NR₇(R₇is hydrogen and lower
alkyl), and Z₂is O and
S, and R in each case₂is hydrogen C_1-4a
Lukil, C._3-4alkenylalkyl, C_1-4haloal
Kyl, cyanoalkyl, cycloalkanylalkyl
le, C_3-4independently selected from alkynylalkyl
However, Z₂is S in both cases.
R₃is C_1-2Must be lower alkyl
}, (In the formula, R_Fouris selected from hydrogen and halogen
), and (In the formula, R_Fiveand R₆is hydrogen, lower alkyl and
and phenyl); −CH₂OH; and −C≡N)]
It is represented by. Compounds of the invention of particular interest as herbicides and
If both X and Y are ester groups, then
R in each ester group of₃are independently 1-3 carbon atoms
The above formula when it is an alkyl group having a child
There is. These preferred 3,5-diesters
Among the compounds, R₁and R₂is dissimilar fluorination
More preferred among those compounds which are methyl radicals
new grouping, and this more preferred grouping.
The most preferred compound in the group is R is 1-5 carbons.
Alkyl or alkylthioal with elementary atoms
A compound that is a kill substituent. The term "alkyl" is used herein to refer to straight and branched chains.
Radical: ethyl, methyl, n-propyl
1-ethylpropyl, 1-methylpropyl,
n-butyl, 2,2'-dimethylpropyl, pentyl
includes isobutyl, isobutyl, and isopropyl;
It is not limited to these. The term ``cycloa''
"Lukil" is cyclopropyl, cyclobutyl, cyclopropyl,
Lopentyl, cyclohexyl, and cyclohep
means a cycloalkyl radical such as chill
intended as a thing. The term "lower alkyl" is used herein to refer to 1-7 carbon atoms.
means an alkyl radical with children. term
"Lower alkenyl" and "lower alkynyl"
Here alkenyl and 2-7 carbon atoms are used.
and an alkynyl group. Such an alkenyl group
Examples are ethenyl, 1-propenyl, 2-propenyl
1-butenyl, 3-butenyl, 2-methyl-
1-propenyl, 2-methyl-2-propenyl,
Includes 1-methylethenyl, etc. above lower grade
Examples of alkynyl are ethynyl, 1-propynyl, 2
-Includes propynyl and the like. The term "saturated and unsaturated heterocyclic groups" refers to O, S,
and 1-3 heteroatoms selected from N
Heterocyclic radical with 3-6 atoms in the ring
meaning, and typically furyl, pin.
lysyl, thienyl, thiiranyl,
xyranyl, and aziridinyl
(aziridinyl), but not limited to
stomach. The term "cycloalkanylalkyl" refers to C_3-6Siku
Alkyl radical substituted by loalkyl radical
intended to mean logical. The term "halo"
"Alkyl" means one or more halogen atoms
also means an alkyl radical substituted with
intended to be. The term "methyl salt fluoride" is used herein to refer to
at least one hydrogen substituted, and by chlorine.
Methyl with at least one hydrogen substituted
means radical. Production of symmetrical pyridine The scheme below will create the symmetrical pyridine (D) of the present invention.
Describe how to do so. It is from dihydropidine (C)
conveniently obtained, and its (C) is in turn the corresponding dihydro
Obtained from xypiperidine (B) by dehydration. suitable
Examples of suitable dehydrating agents include sulfuric acid, toluenesulfonic acid, and
and trifluoroacetic anhydride, but limited to
Not done. Typically dihydroxypiperidine
(B) is the corresponding dihydroxytetrahydropyran (A)
treatment with aqueous or gaseous ammonia.
Obtained by the principle. Desired dihydroxytetrahyde
A suitable aldehyde to obtain dropyran (A)
, a suitable 3-keto ester and a catalytic amount of base.
For example, piperidine or KF and a suitable reaction medium.
React in pawn. This reaction is called dihydroxytetate.
Give lahydropyran and then NH₃or
N.H._FourDihydroxypiperidine by reaction with OH
is obtained, which is then dehydrated to dihydropi
Give lysine (C). dihydroxytetrahydropi
Isolation of ran and dihydroxypiperidine intermediates
Although not necessary in this reaction equation, the following example
It can also be isolated as in some cases. Jihee
As mentioned above, the oxidation of dropyridine (C) is carried out in the present invention.
Gives symmetric pyridine (D). The reaction scheme is further
It explains the reaction ceremony. 4th position is aryl, arylmethyl, phenylmethyl
toxymethyl, or when the heteroatom is oxygen or
by any of the heterocyclic radicals that are sulfur
Where to make substituted dihydropyridine compounds
In some cases, organic acids can be used as dehydrating agents instead of regular inorganic acids.
It is preferred to use a catalytic amount of . typically
is the toluene sulfate in the reaction medium e.g. toluene.
Ponic acid was found to be suitable for this purpose.
It was done. This reaction is generally carried out at reflux temperature;
The water is then removed by azeotropic distillation. 3,4-di
piperidine corresponding to the major amounts of hydropyridine isomers
Trifluoroacetic anhydride is preferred for obtaining from gin.
It is a good dehydrating agent. In this method the reaction medium is typically
chlorinated hydrocarbons such as methylene chloride.
Ru. The above diagram is 2,6- expressed by formula (D)
Bis-substituted-3,5-pyridine-dicarboxylic acid pairs
It conveniently gives the so-called diester. The following formula (In the formula, R, R₁,R₂and R₃are each defined above
as follows, but R₁and R₂are both
C.F.₃The exception is that it cannot be
each R₃are the same and cannot be hydrogen)
The diester compound of the formula
corresponding dihydroxypyridine (R₁and R₂No.1
one has one more fluorine than the product) and non-aqueous
elementary organic bases (e.g. 1,8-diazabicyclo-
[5.4.0]-Undeku-5-en (DBU) or
2,6-lutidine, trialkylamines and pi
Lysine or mono-, di- and trialkyl
(substituted pyridine) and an equimolar mixture of DBU catalyst
neat or of hydrofuran in the presence of amounts of
in a suitable solvent such as or an aromatic solvent such as toluene.
A novel method for reacting in aromatic solvents is dehydrofluoride.
It can be built by the Nation. Similarly, a diester compound of the formula [R₁and
R₂one has two fewer fluorides than the other
(i.e., R₁and R₂One is CF₃and other
is CFH₂)] of the compound thus created
By reduction, it is created as follows: R₁and R₂
One of them is CF₃and the others are CF₂The formula when H
The compound is prepared in a suitable solvent, preferably N,N-dimethyl.
Sodium as a strong reducing agent in chillformamide
Alkali metal borohydride such as borohydride
The corresponding 1,2-dihydro using hydride
reduced to pyridine. obtained in this way
Dihydropyridine is then converted into DBU or 2,
A non-aqueous organic base such as 6-lutidine can be converted to diethyl
or in a suitable solvent such as tetrahydrofuran.
is dehydrofluorinated once again with R₁and
R₂One of them is CF₃Dekatsu and others are CFH₂Corresponding Piri that is
It is made into a gin compound. If you wish, this Natoriu
Mborohydride reduction/dehydrofluorinated
Repeat the order of the₁and R₂one of
is CF₃And the others are CH₃Again, the pyridine compound is
Proceeds via a 1,2-dihydropyridine intermediate
It can be generated by These new and unexpected reactions are presented here.
Used to provide unexpectedly effective herbicides of the present invention
do. The following expression (In the formula, R, R₁,R₂and R₃are each expressed in the above formula.
(as defined in )
The mono-acid compound represented by formula (D) or
Derived by partial (or selective) hydrolysis
be able to. In the formula R₂is difluorome
Chill radical (−CHF₂) Dekatsu R₁is difluoro
If it is not a methyl radical, this difluoro
The ester group adjacent to the methyl radical is R₁next to
Hydrolysis operation leaving the adjacent ester groups intact
selectively removed by If the 3,5-ester groups in the formulas are not the same,
In order to create a new compound, first the following formula (In the formula, R, R₁,R₂and R₃are each expressed in the above formula.
and Hal has the same meaning as chlorine, odor.
means a halogen selected from fluorine and fluorine.
A compound represented by The compound of the above formula contains an excess of the compound of the above formula.
mixed with thionyl halide or other suitable agents
This mixture is then held at reflux for several hours.
It can be built by twisting. The compound of formula is a suitable
Reflux with alcohol for several hours. desired generation
The material is recovered by known methods to ensure that X and Y are non-
Desired compound of the above formula when it is a similar ester
give. Alternatively, a compound of formula and an excess of a suitable alkali
The mixture with the kill halide was
suitable solutions such as lumamide (DMF) or acetone.
4 equivalents of potassium fluoride as a base in a suitable solvent
Alternatively, stir with 1 equivalent of potassium carbonate. about
After 16 hours of constant stirring, the residue was poured into water and then dissolved.
Extract with a chemical agent. Dry this solvent extract and then
to give the asymmetric dicarboxylic acid diester.
I can do it. formula (In the formula, R, R₁and R₂In the above formula,
pyridine dicarboxylic acid (having the same meaning)
suitable pyridine dicarboxylic acid diester
by mixing with excess of a suitable base and a suitable solvent.
Ru. The mixture was kept at reflux for several hours and then concentrated.
Shrink. After concentration, the desired product is recovered and then
The desired pyridine dicarboxylic acid is purified by known methods.
give phosphoric acid. Symmetrical dicarboxylic acids are also those mentioned above.
can be obtained by hydrolysis of the corresponding ester by
Wear. The product is usually recrystallized from a suitable solvent.
Purify properly. The following formula (In the formula, R, R₁and R₂(as defined above)
Compounds of the invention represented by are compounds of formula
reflux conditions with excess thionyl or phosphorous halide
can be made by reacting for several hours with
Ru. The product is concentrated and dried. Symmetric diester compounds of the formula also have the formula
compound and appropriate alcohol under reflux conditions for 15−20
It can also be created by the reaction of time like time.
Wear. Alternatively, 1 equivalent of a compound of formula, an excess of
A mixture of alkyl halide and 2 equivalents of potassium carbonate
The compound is treated with a suitable compound such as N,N-dimethylformamide.
Stir in a suitable solvent for several hours and then pour into water.
The desired product is subjected to known methods of solvent extraction and purification.
Collect more. As can be seen from the above, suitable esters are
carbonyl chloride with a suitable alcohol,
made by mixing to provide the desired ester
Ru. This is the case for symmetric and asymmetric compounds of the above formula.
This is done on both sides. formula (In the formula, R, R₁,R₂,R₃,R_Fiveand R₆is in the formula
(as mentioned above)
Compounds of the invention which have the formula
Produced by reacting with an appropriate amount of ammonia
It will be done. This approach is demonstrated in Examples 88 and 89 below.
It will be done. formula (In the formula, R, R₁,R₂,R₃,R_Fiveand R₆is in the formula
(as defined above)
Compounds of the invention that are treated with excess amine or
By reacting ammonia with a compound of formula
It is made by This approach is shown in Examples 88 and 89 below.
It's the same. formula (In the formula, R, R₁,R₂and R₃is the above formula
(as defined in )
The compounds of the invention have the formula (R_Fiveand R₆are both hydrogen
) with excess dehydrating agent e.g.
It can be made by reacting with phosphorus chloride under reflux.
can. This approach is demonstrated in Examples 92 and 93 below.
It is proved. formula (In the formula, R, R₁,R₂and R₃is the above formula
(as defined by )
The compounds of the present invention can be prepared by removing a compound of formula from excess reducing agent.
For example, reacting with borane in a suitable solvent.
It is created by letting. This method is as below
This is demonstrated in Example 96. Formula XI (In the formula, R, R₁,R₂and R₃is above in Eq.
(as defined above)
The compounds of the present invention are pyridinium compounds of the formula
Methyl chloride with a suitable oxidizing agent such as rolochromate
By reacting in a suitable solvent such as
It can be built. This method is shown in example 97 below.
is demonstrated. Formula XII (In the formula, R, R₁and R₂is defined in the above formula.
The origin expressed by
The light compound has the formula (wherein R_Fiveand R₆is hydrogen
) compound under reflux with excess phosphorus oxychloride
It is created by making it correspond. This method is shown in Example 92.
It is similar to that of . formula (In the formula, R, R₁and R₂is defined in the above formula.
The present invention is represented by
The compound of the formula is combined with an excess of borane and the following
react in a similar manner as described in Example 96 of
It can be created by formula (In the formula, R, R₁,R₂is defined in the above equation
The present invention is represented by
The compound of formula
under agents such as pyridinium, chlorochromate
react in a manner similar to that described in Example 97 of
It is created by The following formula The thioester compound of the present invention having
ol with a compound of the above formula and a normal ester
It is made by reacting in the same way as the production of
Ru. Similarly, the following formula, The dithioester represented by has the above formula
is produced by the reaction of a compound with a suitable thiol.
Ru. In general, the production of various thioester types is
The process is similar to the production of the ester described above. thioester
is illustrated in Examples 140-149. formula, The imidate of the invention represented by
(imidate) Compounds are derived from the corresponding amides in the formula.
Chloroimide is produced through the reaction of mido with thionyl chloride.
and then chloroimide and alcohol.
It is produced by the reaction of This method is shown in Example 152.
It is proven. To prepare the compounds of the present invention, consider the following examples.
It will become clearer, in which, for the most part, Jihi
Droxytetrahydropyran (A), dihydroxypyrane
Peridine (B) and dihydropyridine (C) precursors
Manufacturing isolates each precursor before starting the next synthesis.
A detailed step-by-step example is provided. However,
However, dihydropyridine is a particularly preferred precursor compound.
The desired synthesis is shown in the example jj (“one-pot synthesis”) below.
Therefore, dihydroxytetrahydropyran and dihydroxytetrahydropyran
Achieved without isolation of hydroxypiperidine precursor
It is. This provides the desired dihydropyridine.
According to a preferred method, a suitable 3-ketoester is
2 equivalents, 1 equivalent of the appropriate aldehyde and piperi
A mixture of catalytic amounts of ginseng was left at 40-100°C.
or a suitable solvent (e.g. methylene chloride or trichloride).
The first reaction is to react for 4-20 hours in
It will be done.¹⁹F The reaction is complete as indicated by NMF analysis.
After completion, a suitable solvent is added to the product and then the gas
Storous ammonia is mixed until the second reaction is complete
sent into things. The reaction mixture is then drained of excess acetate.
It is purged with nitrogen gas to remove ammonia.
The reaction mixture was then soaked in ice water before treatment with concentrated sulfuric acid.
Cooled in bath to 5-10°C. 10 minutes of reaction mixture
After 2 hours of mixing, pour the mixture over crushed ice and sprinkle with salt.
Separate the dichloromethane layer, dry and concentrate to obtain the desired diluted
Hydropyridine is obtained. This method of operation allows you to
Hydropyridine is prepared by combining the precursor, dihydropyridine, and
Droxytetrahydropyran and dihydroxy
Made without isolation of piperidine. desired dihydre
Lopyridine is thus obtained in good yields. Dihydroxytetrahydropyran, before structure A
"Journal of Organi" to create a skeleton
"Tsuku Chemistry" Volume 30, page 3237 (1965)
The method described by Day et al. can be used.
According to this method, an appropriate aldehyde can be converted into an appropriate 3
- a ketoester and a catalytic amount of piperidine and appropriate
The reaction can be carried out with or without a suitable reaction medium.
Ru. Production of dihydroxytetrahydropyran The following examples a-m are structures (A) shown in the above diagram.
provides an exemplary method for producing a precursor compound of Example a diethyl 2,6-bis(trifluoromethyl)
-2,6-dihydroxy-4-propyl-tet
lahydro-3,5-pyranedicarboxylate 20g (0.278 mol) of buchi in a 500ml single-necked flask
Ruraldehyde, 102 g (0.555 mol) ethyltri
fluoroacetoacetate and approximately 150ml of eta
Charge the knoll. To this, 3g (0.0156 mol)
Add potassium fluoride. Mix this mixture at room temperature for 18
Stir for an hour. Concentrate this material and then ethyl
Dilute with ether. Wash, dry, and concentrate organic materials.
Shrink to give a white powder. This crude product was dissolved in hot methane.
13g (13.7%) recrystallized from cyclohexane
gives a product with a m.p. of 128-132°C. analysis. C₁₆H_{twenty two}O₇F₆as Calculated value: C43.63, H5.00 Actual value: C43.58, h5.04 Example b diethyl 2,6-bis(trifluoromethyl)
-2,6-dihydroxy-4-isobutyl-te
Trihydro-3,5-pyranedicarboxylate
to 80% purity methyl trifluoroacetoacetate
280 g (2.0 mol) and 86 g of isovaleraldehyde
(1.0 mol) and mechanically stir the mixture. fever
The reaction takes place and the temperature of the reaction mixture reaches 105°C.
After 5 hours of stirring, the reaction mixture was poured into 450 ml of hexane and
and 30 ml of ether, then
The first group with m.p. 83-87°C was cooled in a Lye ice bath
1.68g and m.p. 67-73℃ second group 14.51g.
Ru. Group 1 is a 2:1 mixture of cis and trans isomers.
It is a compound. Concentrate the mother liquor to give 344 g of residue.
However, this is due to the cis and trans heterogeneity of the desired product.
It is a crude mixture of sexual bodies. This cis isomer has two esters in the cis position.
has structure A1 with a trans
The isomers are two in trans position to each other as shown below.
has structure A2 with an ester group of: Following the method described in example a, select a suitable alkaline
Dehyde with appropriate trifluoroacetoacetate
By reacting, another compound is created.
and are listed in Table 1. 【table】 Production of dihydroxypiperidine To make dihydroxypiperidine precursor (B), four steps are required.
Two different methods can be used. The first method (method
) is 2 equivalents of 3-ketoester, suitable alde
1 equivalent of hydride and 1.5 equivalents of ammonium hydroxide
The mixture was refluxed in ethanol for 4-18 hours.
and then concentrated to obtain B similar to the literature method.
Ru. The second method (Method) (“Journal of He
"Terocyclic Chemistry" Volume 17 1109
(Page, 1980), the structure A of dihydroxytetrahydryl
1 equivalent of dropyran, aqueous ammonium hydroxide
A mixture of 1.5 equivalents and appropriate amounts of ethanol
-Stir at room temperature for 18 hours, but alternatively maintain at reflux.
and then concentrated. This residue is extracted from a suitable solvent.
by recrystallization or other suitable methods of purification.
Obtain (B). In the third method, a suitable solvent (and
For example, tetrahydrofuran, toluene or chloride
dihydroxytetrahydride of structure (A) in methylene)
In a solution of ropiran,¹⁹F NMR analysis shows complete reaction
Flow of gaseous ammonia for several hours until directed
Pass. Concentrate the reaction mixture and then dissolve the residue in a suitable
Recrystallize from a solvent or perform appropriate purification.
to obtain a precursor of structure (B). In the fourth method, a suitable 3-ketoe
2 equivalents of ster, 1 equivalent of the appropriate aldehyde and
and piperidine in catalytic amounts together with a suitable solvent.
at 40-100℃ with or without¹⁹F NMR analysis
for several hours or days until a complete response occurs.
Stir. After completing the first step of the method, if
If this first step reaction is carried out without solvent
If necessary, a suitable solvent is added to the reaction mixture. aqueous
The flow of ammonia gas,¹⁹F NMR is completely anti-
40-70 hours (usually about 6-10 hours)
Send into solution at °C. The reaction mixture was concentrated and then
This residue is recrystallized from an appropriate solvent to obtain the precursor structure.
Obtain (B). The method gives a higher yield of the desired product
This is the preferred method. Method - To further illustrate, use the following example n.
−ff is given. Example n Dimethyl 2,6-bis(trifluoromethyl)
-2,6-dihydroxy-4-isobutyl-
Production of 3,5-piperidinedicarboxylate In 500 ml of tetrahydrofuran (THF), Example b
A solution of 344 g (0.920 mol) of the crude product from
58 g (3.41 mol) of ammonia is passed for 3 hours.
Ru. The reaction mixture was concentrated and the residue (332
g) was recrystallized from hexane-ether to give a white solid.
53.7 g of desired product (m.p. 102-106°C)
Yield 13 from trifluoroacetoacetate
%). analysis. C₁₅H_{twenty one}F₆N₁O₆about Calculated values: C, 42.36; H, 5.00; N, 3.29. Actual value C, 42.84; H, 4.94; N, 3.29. Concentrate the mother liquor to obtain a large amount of crude desired product. Example o Dimethyl 2,6-bis(trifluoromethyl)
-2,6-dihydroxy-4-(2-furyl)-
Production of 3,5-piperidinedicarboxylate 60ml of ethanol in a 500ml three-neck flask,
29.07 g (0.3 mol) of 2-furaldehyde and
110 g (0.6 mol) ethyl trifluoroacetoa
Charge the cetate. Cool the reaction mixture in an ice bath
and then 21.15 g (0.35 mol) of aqueous ammonium hydroxide
Slowly add the monium with stirring. this mixture
Heat under reflux for 2 hours and then cool. Obtained
The resulting precipitate is filtered and then reconstituted from hot ethanol.
Crystallized to 53.34 g (39%) m.p. 129-131°C.
Give crystals. analysis. C₁₇H₁₇F₆N₁O₇of Calculated values: C, 44.06; H, 4.10; N, 3.02. Actual value C, 44.04; H, 4.12; N, 3.03. Example p diethyl 2,6-bis(trifluoromethyl)
-2,6-dihydroxy-4-propyl-3,
Production of 5-piperidinedicarboxylate 150-200ml of ethanol in a 500ml round bottom flask
and 40 g (0.0909 mol) of the product of Example a.
Ta. While stirring this mixture with a magnetic stirrer,
% aqueous ammonium hydroxide 8.23g (0.136mol)
Slowly add to the flask. Add this mixture to nitrogen.
Stir under water for 18 hours. Filter the precipitate and m.
p.140-142℃ 17.83g (44.68%) of desired product
generate. analysis. C₁₆H_{twenty three}O₆N₁F₇attached Calculated values: C, 43.73; H, 5.23; N, 3.18. Actual values: C, 43.67; H, 52.6; N, 3.19. Example q trans-diethyl-2,6-dis(difluoro)
(methyl)-2,6-dihydroxy-4-iso
Butyl-3,5-piperidinedicarboxylate
to Ethyl difluoroacetoacetate
25.0g (0.150mol) of (EDFAA) and isobarrel
In a mixture with 8.04ml (0.075 mol) of aldehyde
Add 2 ml of piperidine. Reaction mixture is exothermic
At this point, the temperature of the mixture reaches 86°. this
After the reaction mixture has cooled down to room temperature, it is
Treat with THF (100ml). gaseous NH₃of,¹⁹F
THF solution above until NMR indicates complete reaction.
pump into the liquid. This reaction mixture is combined with the desired product and
32.77 g (100
%). Crystallize this oil from hexane
to give a solid. Part of this solid (5.0g) was
dissolves in water. Wash the ether solution with water and dry
(MgSO_Four) and then concentrated to oil, but this
If left untreated, it will crystallize. Reconsolidation from hexane
The desired product is crystallized as a white solid (m.p. 98−100℃)
gives 1.0g (22.8%) as This substance is¹⁹F
Identified as trans isomer by NMR. analysis. C₁₇H₂₇F_FourN₁O₆about Calculated values: C, 48.92; H, 6.52; N, 3.36. Actual values: C, 48.93; H, 6.51; N, 3.31. Example r diethyl 2,6-bis(trifluoromethyl)
-2,6-dihydroxy-4-butyl-3,5
-Manufacture of piperidine dicarboxylate In a 500 ml three-necked flask, add 40% of the product from Example d in Table 1.
g (0.0881 mol) and about 200-250 ml of THF.
Enter. This flask contains two dry ice creams.
with the nitrogen condenser and nitrogen inlet installed.
Ru. Add 5 g (0.294 mol) of ammonia gas to the above solution.
Bubble into the liquid and stir the solution for 18 hours.
do. Concentrate the organic matter and dilute with ethyl ether.
diluted, washed with water, and anhydrous MgSO_FourLet it dry on top, then
and concentrate. Grind this residue with n-hexane.
Crush and filter the desired product m.p. 77-80℃
Gives 7.57g (19%). analysis. C₁₇H_{twenty five}F₆N₁O₆about Calculated values: C, 45.03; H, 5.51; N, 3.09. Actual values: C, 44.96; H, 5.58; N, 3.03. Structure B of 2,6-dihydroxypiperidine
Still other examples were made according to the above method of Examples n-r.
and are listed in Table 2. 【table】 【table】 Production of dihydropyridine The dihydropyridine precursor of structure (C) is
Add hydroxypiperidine to a dehydrating agent such as concentrated sulfuric acid.
(method) or trifluoroacetic anhydride (method)
) or by dehydrating with
Azeotroping of water using luenesulfonic acid as a catalyst
Obtained by removing (method). To further illustrate the above method, the following example
Describe gg-fff. Example gg diethyl 2,6-bis(trifluoromethyl)
-1,4-dihydro-4-isobutyl-3,5
-Pyridine-dicarboxylate and its 3,4
- of a 2:1 mixture with dihydropyridine isomers
manufacturing Ice water with 200ml concentrated sulfuric acid and 200ml methylene chloride
48.7 g (0.115 mol) of the product of example n to the cooled mixture
Add all at once. Stir the reaction mixture for 20 minutes.
Pour into 1 cup of ice water. Separate the methylene chloride layer;
Wash once with 100 ml of saturated sodium bicarbonate solution and dry.
Dry and then concentrate to obtain 28.0 g (64.6%) of the crude product.
give. A portion (5.0 g) of this product was added to 0.5 tons.
Kugel rolls (pot temperature 120℃)
(kugelrohr) Distillation D^{twenty five} _D1.4391 desired product
Gives 4.8g. analysis. C₁₅H₁₇F₆N₁O_Fourabout Calculated value: C46.28; H4.40; N3.60. Actual value: C46.39; H4.44; N3.60. Example hh Diethyl 2,6-bis(difluoromethyl)-
1,4-dihydro-4-isobutyl-3,5-
Production of pyridine carboxylate Crude cis and trans mixture of the products of example q
5.0g (0.012mol) in 10ml trifluoroacetic acid free
Stir with water. The temperature of this reaction mixture is 36℃
Rise. After this temperature has fallen to room temperature,
Concentrate the reaction mixture. Dissolve this residue in ether
and then saturated NaHCO₃Wash and dry with
(MgSO_Four) and then concentrated in oil (3.76g, 82.3%).
Shrink. This oil is 10% ethyl acetate/cyclo
Cleaned by HPLC using hexane as eluent.
Romatographed 1.73 g of desired product
(37.8%) n^{twenty five} _DGive as 1.4716 oil. analysis. C₁₇H_{twenty three}F_FourNO._Fourabout Calculated value: C53.54; H6.08; N3.67. Actual value: C53.38; H6.40; N3.25. Example ii diethyl 2,6-bis(trifluoromethyl)
-1,4-dihydro-4-(2-thienyl)-
Production of 3,5-pyridinedicarboxylate Approximately 100ml of toluene
Reflux using a Dean-Stark trap.
Remove water. To this cooled toluene, the
20 g (0.0418 mol) of the product of example w and p-tol
Add 2.0 g (0.0105 mol) of ensulfonic acid.
Heat this mixture to reflux temperature and reflux for 5.5 hours
Ru. Cool and filter the solution. By distilling off the solvent
The product was diluted with 20% ethyl acetate/cyclohexane.
Chromatograph using xane as eluent
put on. Product weight: 2.45g (13.3%), n^{twenty five} _D
1.4937. analysis. C₁₇H₁₅O_FourN₁F₆S₁about Calculated values: C46.04; H3.38; N3.16; S7.22. Actual value: C46.11; H3.44; N3.12; S7.16. Preferred method to provide the desired dihydropyridine
2 equivalents of the appropriate 3-keto ester,
1 equivalent of the appropriate aldehyde and a catalytic amount of piperidine
A mixture of
4-20 with or without
A first reaction is prepared for a time reaction. The reaction
¹⁹Completed as shown by F NMR analysis
After that, methylene chloride is added to the product and then gas
ammonia into the mixture until the second reaction is completed.
Pass during the meeting. The reaction mixture was then purged with nitrogen.
Remove excess ammonia. This reaction mixture
Then cool to 5-10℃ in an ice water bath and add concentrated sulfuric acid.
Process by. This reaction mixture was heated for 10 minutes to 2 hours.
After stirring for an hour, the mixture was poured onto crushed ice and diluted with methylene chloride.
Separate the layer, dry, and concentrate to obtain the desired dihydrochloride.
Give pyridine. This mode of operation
Hydropyridine is an intermediate dihydroxytetrahydride
Isolate ropyran and dihydroxypiperidine.
It is produced in one reaction vessel. desired dihydre
Lopyridine is therefore obtained in good yield. The above
The following example is provided to illustrate how to do this. example jj diethyl 2,6-bis(trifluoromethyl)
-1,4-dihydro-4-ethyl-3,5-pi
Lysine dicarboxylate and its 3,4-
One-pot mixture of dihydropyridine isomers
synthesis 368g of ethyl trifluoroacetoacetate
(2.0 mol), 58 g (1.0 mol) of propionaldehyde
1 ml of methylene chloride 400
ml of the mixture at 20°C for 1 hour, then at 30°C for 1 hour.
reflux for 1 hour and then cool. Professional
Additional pionaldehyde 16.8g (0.289mol)
was added to the above mixture and then continued to reflux for 2 hours.
do. Remove heating mantle. ammonia gas
108 g (6.35 mol) are passed through the reaction mixture in 2 hours.
The reaction mixture was stirred at 20 °C for 40 h and then diluted with ice water.
Cool inside. 100 ml of concentrated sulfuric acid to this reaction mixture
was carefully added over 20 minutes, followed by the addition of concentrated sulfuric acid.
Add 300ml in 10 minutes. Add the reaction mixture to 4 beads.
Pour into a car over 600g of crushed ice. methylene chloride layer
Separate and dry (MgSO_Four), then concentrated to the desired
of the product and its 3,4-dihydro isomer.
gives 386 g of oil containing the compound. Thicken this oil
Vigorous stirring of 300 ml of sulfuric acid and 300 ml of methylene chloride
Add to the prepared mixture. Stir this mixture for 30 minutes
Then, pour over 1 kg of ice. methylene chloride layer
Separation, drying (MgSO_Four), concentrated to give 348g of oil.
This oil is mixed with 400 ml of petroleum ether.
Crush to remove 9.5 g of undissolved solids. then
Concentrate the petroleum ether filtrate. The remainder is 0.4t
Kugelrohr distillation with 290 g of oil (74.5
%), but this oil¹⁹By F NMR analysis
Measured to contain 1,4-dihydro (84%) and its 3,4
- dihydro (16%%) isomer.
The product mixture is more than 90% pure. Addition of dihydropyridine of structure (C) in the diagram
The additive examples were constructed according to the method described above in Examples gg to jj.
are listed in Table 3. All examples in Table 3
R at₃is ethyl. 【table】 【table】 The following examples illustrate specific new herbicides according to the present invention.
Production of herbicides and intermediates for the production of herbicides
illustrative of, but not limited to,
It's not. Symmetrical 3,5-pyridinedicarboxy according to the diagram
Corresponding dihydropyridine to make sylate
C is treated with sodium nitrite in acetic acid. The above procedure is illustrated by Examples 1-11. Example 1 Diethyl 2,6-bis(trifluoromethyl)
Production of -4-ethyl-3,5-pyridinedicarboxylate 35 ml of glacial acetic acid and 13.89 g in a 250 ml flask
(0.0354 mol) of diethyl 2,6-bis(trifluoromethyl)-4-ethyl-1,4-dihydro-3,5-pyridinedicarboxylate. Sodium nitrite is added in an amount of 3 g (0.0434 mol) and the mixture is stirred under nitrogen for 72 hours. Pour the solution onto ice water and stir. Extract the organics with ether and wash them with saturated aqueous sodium bicarbonate. The organics were then dried over anhydrous magnesium sulfate, filtered and concentrated to 4.93
g (35.67%) of product are obtained. mp33−35℃. Calculated values for analysis C ₁₅ H ₁₅ O ₄ N ₁ F ₆ : C.46.51; H.3.87; N.3.61. Actual value: C.46.54; H.3.90; N.3.63. Example 2 Diethyl 2,6-bis(trifluoromethyl)
Preparation of -4-methyl-3,5-pyridinedicarboxylate Place 20 ml of glacial acetic acid in a 50 ml round bottom flask.
To this was added 5 g (0.0133 mol) of diethyl 2,6-bis(trifluoromethyl)-4-methyl-1,4
-dihydro-3,5-pyridinedicarboxylate is added, followed by the slow addition of 3 g (0.0434 mol) of sodium nitrite. The flask is immediately fitted with a condenser and nitrogen tubing and stirring is continued for 18 hours before pouring the mixture onto crushed ice and water. The organics are extracted twice with ether, washed once with saturated brine, and then twice with saturated aqueous sodium bicarbonate. The organic matter was dried over anhydrous magnesium sulfate and concentrated to 2.16 g (43.5
%) of product. mp55−58℃. analysis. Calculated values for C ₁₄ H ₁₃ F ₁₆ NO ₄ : C.45.05; H.3.48; N.3.75. Actual value: C.44.95; H.3.56; N.3.75. In a similar manner as described in Examples 1 and 2 above,
However, other pyridine dicarboxylates can be made using the appropriate starting materials and reaction conditions instead. The same or equivalent solvents, bases and catalysts, along with appropriate temperatures and times, are readily employed in carrying out these methods. Typical compounds made according to the above method are shown in Table 4 along with certain of their physical properties. TABLE TABLE The following Examples 12-27 illustrate a new way to prepare the compounds of the invention represented by the formulas. Example 12 Preparation of diethyl-2-(difluoromethyl)-4-ethyl-6-(trifluoromethyl)-3,5-pyridinedicarboxylate 1558 g (4.00 mol) of diethyl 2,6-bis(trifluoromethyl) -1,4-dihydro-4-
ethyl-3,5-pyridinedicarboxylate,
628 g (4.0 mol) of 1,8-diazabicyclo-
[5.4.0]-Undeku-5-ene (DBU) and 500
A mixture of ml of tetrahydrofuran is kept at reflux for 19 hours, cooled and then poured into a mixture of 2 Kg of ice and 250 ml of concentrated hydrochloric acid. The organic layer is separated and the aqueous layer is extracted twice with 500 ml of CH ₂ Cl ₂ . The combined organics are dried (MgSO ₄ ) and then concentrated. The remainder was 1158g (78.5%) after Kugelrohr distillation at 1 Torr (pot temperature of 150-160℃).
gives the desired product, n ²⁵ _D 1.4458. analysis. Calculated values _{for C15H16F5NO4} : C48.78; _H4.37 ; _N3.79 . Actual value: C48.75; H4.29; N3.72. Example 13 Diethyl 2-(difluoromethyl)-4-n-propyl-6-(trifluoromethyl)-3,5-
Preparation of pyridine dicarboxylate 20.0 g (0.05 mol) diethyl 2,6-bis(trifluoromethyl)-1,4-dihydro-4-
n-propyl-3,5-pyridinedicarboxylate, 7.62 g (0.05 mol) DBU and 200 ml
Keep the THF at reflux for 9 hours, cool, and add 500 ml of ice water.
Pour it inside. Mixture in ether (2 x 200ml)
Extract with The ether extract was washed with dilute hydrochloric acid,
Dry (MgSO ₄ ) and then concentrate to give the desired product.
Gives 12.4g (64.5%). n ²⁵ _D 1.4436. analysis. _Calculated values _{for C16H18F5N1O4} : C50.13; _H4.73 ; _N3.65 . Actual value: C49.92; H4.71; N3.58. Example 14 Dimethyl 2-(difluoromethyl)-6-(trifluoromethyl)-4-isobutyl-3,5-
Preparation of pyridine dicarboxylate (a) Reaction of the product of example gg with DBU 23.0 g (0.0591 mol) of the product of example gg, 12.2 g (0.077 mol) of 96% pure DBU and 100 ml of THF
The mixture was kept at reflux for 3 days, then 3N HCl
Pour into 250ml of water. The oil precipitate is extracted into ether (2 x 100 ml). This ether extract was dried (MgSO ₄ ) and concentrated to 14.4 g.
gave an oil containing the desired product and an acidic product according to ¹ H NMR. This oil is dissolved in ether and then extracted with 100 ml of saturated sodium bicarbonate solution. The ether layer is dried (MgSO ₄ ) and then concentrated to give 8.9 g of oil, which is 71% pure desired product (by ¹⁹ F NMR). The sodium bicarbonate extract is acidified with concentrated HCl to give an oil, which is extracted into ether. The ether layer is dried (MgSO ₄ ) and concentrated to give a residue of 4.8 g containing monocarboxylic and dicarboxylic acids (9:1) derived from the desired product. This residue is 3.0g
(0.0217 mol) of potassium carbonate, 20 ml of methyl iodide and 50 ml of acetone. The mixture is kept at reflux for 42 hours and then concentrated.
This residue was treated with water and then ether (2×
Extract with 100ml). Dry this ether layer,
Concentrate. Add 1 torr of this residue (pot temperature 130
Desired product by Kugelrohr distillation at )
Give 5.1g (23.4% from e.g. gg) as oil,
n ²⁵ _D 1.4478. This product crystallizes after standing;
mp36−37℃. analysis. _{Calculated values for C15H16F5N1O4} : C48.79; _H4.37 ; N3.79. Actual value: C48.75; H4.39; N3.77. The desired product of 71% purity as described above was chromatographed by HPLC using 3% ethyl acetate/cyclohexane as the eluent stream to give an initial fraction (0.79 g, residence time 7-8.5
), which was identified as methyl 6-(difluoromethyl)-4-(isobutyl)-2-(trifluoromethyl)-3-pyridinecarboxylate. The second fraction (residence time 8.5-18.5 minutes) added 6.4 g of pure desired product.
(29.4%) and n ²⁵ _D 1.4474. (b) Reaction of the product of example gg with tributylamine A mixture of 38.9 g of the 80% pure product of example gg and 20.5 g of tributylamine is heated to 155° C. for 30 minutes. Cool the reaction mixture to 30°C and then add 100ml
diluted with toluene. This toluene solution
Successive washes with 6N hydrochloric acid, saturated sodium bicarbonate and brine, drying and concentration give 36.4 g of 73% pure product corresponding to 86% yield.
This reaction can be carried out in excess (10 equivalents) of tributylamine with essentially the same effect. (c) Reaction of the product of example gg with tributylamine in toluene A mixture of 38.9 g of the 80% pure product of example gg, 20.4 g of tributylamine and 30 ml of toluene is
Heat to 115°C for 1 hour and 40 minutes at 115°C. The reaction mixture was cooled and treated as in (b) to yield 76%, corresponding to 90% yield.
Gives 36.3 g of pure product. (d) Reaction of the product of example gg with triethylamine A mixture of 11.8 g of the 80% pure product of example gg and 3.34 g of triethylamine is heated at 100°C for 10 minutes and then at 125°C for 10 minutes. The reaction mixture was cooled and treated as in (b) to give 8.14 g of 76% pure product, corresponding to a 63% yield. (e) the product of Example gg in the presence of a catalytic amount of DBU and 2,
Reaction with 6-lutidine Example 5.0 g of the product of gg and 2.13 g of 2,6-lutidine
Heat the mixture with g at 143°C for 30 minutes. DBU
were added and the reaction mixture was incubated for another hour 30
Heat for 1 minute, cool and process as in (b) to give 4.23 g of the desired product. The reaction is characterized by an excess of 2,6-lutidine and a catalytic amount of DBU,
It can also be carried out without a solvent or in the presence of toluene as a solvent to give similar results. Example 15 Diethyl 2-(difluoromethyl)-4-isopropyl-6-(trifluoromethyl)-3,5-
Production of pyridine dicarboxymate Diethyl 2,6-bis(trifluoromethyl)
-,4-dihydro-4-isopropyl-3,5-
Pyridine dicarboxylate 50.0g (0.124mol), DBU18.87g (0.124mol) and THF200
ml of the mixture is kept at reflux for 18 hours, then poured into water and extracted with ether. The ether extract was washed with dilute hydrochloric acid, dried (MgSO ₄ ),
Then concentrate. The residue was subjected to Kugelrohr distillation at 1 Torr to give 17.97 g (37.8 g) of the desired liquid product.
%), giving n ²⁵ _D 1.4465. analysis. _Calculated values _{for C16H18F5N1O4} : C50.13; _H4.73 ; _N3.65 . Actual value: C50.16; H4.76; N3.65. Example 16 Production of diethyl 2-(difluoromethyl)-4-isobutyl-6-(trifluoromethyl)-4-isobutyl-6-(trifluoromethyl)-3,5-pyridinedicarboxylate Diethyl 2,6-bis (trifluoromethyl)
-1,4-dihydro-4-isobutyl-3,5-
Pyridine dicarboxylate 10.0g (0.0240mol), DBU3.65g (0.0240mol) and THF150
ml of the mixture is kept at reflux for 18 hours and then concentrated. Dissolve the residue in ether, wash with dilute hydrochloric acid,
Dry (MgSO ₄ ) and concentrate. This residue is Kugelrohr distilled at 0.1 Torr to give 4.80 g (50%) of the desired product as an oil, n ²⁵ _D 1.4436. analysis. _Calculated values _{for C17H20F5N1O4} : C51.39; _H5.07 ; _N3.53 . Actual value: C51.35; H5.08; N3.51. Example 17 Diethyl 2-(difluoromethyl)-4-cyclopropyl-6-(trifluoromethyl)-3,5
-Production of pyridinedicarboxylate diethyl 2,6-bis(trifluoromethyl)
-2,6-dihydroxy-4-cyclopropyl-
55.5 g (3.26 mol) of ammonia are introduced into a solution of 40 g (0.0916 mol) of tetrahydropyran-3,5-dicarboxylate in 200 ml of THF. The reaction mixture is concentrated to give 38.5 g (96.7%) of solid.
A portion (28 g) of this material is stirred with 27.08 g (0.129 mole) of trifluoroacetic anhydride for one day. Concentrate the reaction mixture and dilute with ether. The ethereal solution was washed with saturated sodium bicarbonate, dried (MgSO ₄ ), and concentrated to 21 g (81.3%).
of oil, giving n ²⁵ _D 1.4460. This oil is diethyl 2,
6-bis(trifluoromethyl)-4-cyclopropyl-1,4-dihydro-pyridine-3,5-
Identified as a dicarboxylate. A portion of this oil (18g) and 150mg of THF to 68.2g of DBU
(0.0449 mol). The reaction mixture is kept at reflux for 24 hours and then concentrated. The residue is stirred with water and then extracted with ether. The ether extract was washed with dilute hydrochloric acid, dried (MgSO ₄ ),
Concentrate. This residue was crystallized to yield 13 g of crude product.
(76.0%). A portion of this product (2.0
Recrystallization of g) from petroleum ether at low temperature gives 1.17 g (85%) of the desired product, mp30−32
℃. analysis. _Calculated values _{for C16H16F5N1O4} : C50.40; _H4.23 ; _N3.67 . Actual value: C50.48; H4.32; N3.78. In a similar manner to Example 12, the asymmetric pyridine compounds of the present invention are prepared as shown in Table 5. [Table] [Table] Xylate

Example 27 Diethyl-2-(difluoromethyl)-4-(2,
Preparation of 2-dimethylpropyl)-6-(trifluoromethyl)-3,5-pyridinedicarboxylate 3.11 g of pyridinium chlorochromate are dissolved in 11.0 g (0.105 mol) of 3,3-dimethylbutanol in 20 ml of methylene chloride. (0.15 mol) is added. The methylene chloride solution is decanted and then filtered through a silica gel column. Wash this silica gel column with 200 ml of methylene chloride. The combined methylene chloride solutions were concentrated under reduced pressure at 20°C.
This gives 3.7 g of a residue which is 66% pure 2,2-dimethylenebutyraldehyde. A mixture of the above aldehyde, 14 g (0.076 mol) ethyl trifluoroacetoacetate, 0.5 ml piperidine and 50 ml THF is kept at reflux for 3 days and then cooled to room temperature. 36 g of ammonia is passed through the THF solution for 1 hour. The reaction mixture is stirred with 100 ml of water and 100 ml of ether. Separate, dry, and concentrate the ether layer to a residue of 14.9
give g. The residue is poured into a cold mixture (10° C.) of 50 mg concentrated sulfuric acid and 50 mg methylene chloride. The mixture is stirred for 10 minutes and then poured onto 300 g of crushed ice. Separate, dry, and concentrate the methylene chloride layer.
The residue is subjected to Kugelrohr distillation at 0.4 Torr. Discard the initial fraction (pot temperature 90°C).
The second fraction (pot temperature 120℃) is 5.3g of oil.
and 10% ethyl acetate/
Purified by HPLC using cyclohexane. The first fraction is diethyl 2,6-bis(trifluoromethyl)-1,4-dihydro-4-
A syrup identified as (2,2-dimethylpropyl)-3,5-pyridinedicarboxylate
It is 4.83g. 3.83g (0.0089mol) of this syrup, 1.41g (0.0089mol) of DBU and 50ml of THF
is kept at reflux for 20 hours and then concentrated. the remainder
Stir with 100 ml of 6N HCl and 100 ml of ether and filter. The ether filtrate is separated and successively washed with water, saturated sodium bicarbonate, saturated sodium chloride, then dried and concentrated. The residue is subjected to Kugelrohr distillation at 1 Torr (pot temperature 130°C) to give 1.9 g of oil, which is purified by HPLC using 3% ethyl acetate/chloride as eluent. The initial fraction is discarded. The second fraction gives 1.4 g of the desired product, n ²⁵ _D 1.4522. analysis. _Calculated values for _C18H22F5N1O4 : _C52.55 ; _H5.39 ; _N3.40 . Actual value: C52.54; H5.42; N3.40. Examples of monoacid compounds represented by the formula are as follows:
28-37, made by selective hydrolysis of diester compounds of formula. Example 28 2-(difluoromethyl)-4-ethyl-6-
Preparation of (tohyfluoromethyl)-3,5-pyridinedicarboxylic acid, 5-ethyl ester 18.5 g (0.050 mol) of the product of Example 12, 3.3 g (0.072 mol) of 85% potassium hydroxide and ethanol
100 ml of the mixture is stirred for 18 hours and then poured into water. The reaction mixture is extracted with 200 ml of ether. Acidify the aqueous layer with 50 ml of concentrated hydrochloric acid. The oily precipitate was extracted into ether (2 x 100ml) and
This ether extract was then dried (MgSO ₄ ) and
Concentrate. The remaining solid was recrystallized from ether-petroleum ether to give 14.4 g (84.7%) of the desired product, mp 117-120°C. analysis. _{Calculated values} for _C13H12F5N1O4 : _C45.76 ; _H3.54 ; N4.10. Actual value: C45.77; H3.42; N4.09. Example 29 2-(difluoromethyl)-4-propyl-6-
Preparation of (trifluoromethyl)-3,5-pyridinedicarboxylic acid, 5-ethyl ester 32 g (0.0835 mol) of the product of Example 13 and 150 ml
of ethanol into a 500 ml flask. In a separate flask, 5.51 g of 85% potassium hydroxide (0.0835
mol) and 75 ml of water. This water-based
Pour the KOH into the 500 ml flask and heat the mixture to reflux for 18 hours. The reaction mixture is concentrated and then stirred into water. The aqueous solution is acidified with concentrated HCl and then extracted with ethyl ether. Dry the organics over anhydrous MgSO ₄ , filter and concentrate to yield 23.15 g (78%) of the desired product, m.p98
−100℃. analysis. _Calculated values _{for C14H14O4N1F5} : C47.32; _H3.98 ; _N3.94 . Actual value: C47.45; H3.99; N3.95. Example 30 2-(difluoromethyl)-4-isobutyl-6
Preparation of -(trifluoromethyl)-3,5-pyridinedicarboxylic acid, 5-methyl ester 6.4 g (0.0173 mol) of the product of Example 14, 85%
A mixture of 1.2 g (0.0182 mol) KOH, 30 ml methanol and 2 ml water is stirred for 2 days and then concentrated.
The residue was stirred with 200 ml of water and then extracted with ether. The aqueous layer is acidified with concentrated HCl while the oily precipitate is extracted with ether (2 x 100 ml). The ether extract was dried and concentrated to give 5.9 g of solid, which was recrystallized from hexane.
Gives 4.9 g of the desired product as a solid, mp100−
102℃. analysis. _Calculated values _{for C14H14F5N1O4} : C47.33; _H3.97 ; _N3.94 . Actual value: C47.40; H3.97; N3.90. In a similar manner to Examples 28, 29 and 30, other 2-(difluoromethyl)-6-(trifluoromethyl)-3,5-pyridinedicarboxylic acid 5-ethyl esters of the invention are illustrated in Table 6. prepared by hydrolysis of the starting materials listed. [Table] In the present invention, the pyridinecarboxylic acid of the formula
Compounds of (D) and are prepared by complete hydrolysis as illustrated by Examples 38-43 below. Example 38 Preparation of 2,6-bis(trifluoromethyl)-4-ethyl-3,5-pyridinedicarboxylic acid 10 g (0.025 mol) of the product of Example 1 and 100 ml of 10%
Aqueous KOH is charged into a single-necked flask. The mixture was refluxed for 48 hours, then the aqueous mixture was extracted twice with ether, dried over _MgSO4 , and then concentrated to give 2.73 g (32.23%) of the desired product, mp 263-269 °C ( Disassembly). _Calculated for analysis _C11H7O4N1F6 : _C39.87 ; H2.11; _N4.22 ; _F34.44 . Actual value: C39.92; H2.22; N4.17; F34.60. Example 39 2-(difluoromethyl)-4-n-propyl-
Preparation of 6-(trifluoromethyl)-3,5-pyridinedicarboxylic acid 20.1 g (0.0525 mol) of the product of Example 13, 85%
A mixture of 11.4 g of KOH and 100 ml of methanol
Hold at reflux for an hour and then concentrate. 200 remaining
ml of water and then extracted with ether. The aqueous layer is separated and acidified with 30 ml of concentrated hydrochloric acid. The oily precipitate is extracted into ether and the ether extract is concentrated to dryness. Recrystallization of the residue from chloroform gives 4.2 g (24%) of the desired product.
mp235.5−236.5℃. analysis. Calculated values _{for C12H10F5NO4} : C44.05; _H3.08 ; _N4.28 . Actual value: C43.92; H2.98; N4.19. The combined mother liquor was concentrated, and the remaining was 10 g of KOH.
Treatment as above with 50 ml of methanol and 2 ml of water gives an additional 2.2 g (12%) of the desired product. Example 40 6-(difluoromethyl)-4-ethyl-2-
Preparation of (trifluoromethyl)-3,5-pyridinedicarboxylic acid A flask is charged with 60 g (0.163 mol) of the product of Example 12 and 200 ml of methyl alcohol. In a separate flask, combine 150 ml of water and 21.52 g (0.326 moles) of potassium hydroxide. This aqueous KOH
into the above flask and heat the mixture to reflux overnight. The reaction mixture is cooled and extracted once with ethyl ether. Acidify the aqueous layer with concentrated hydrochloric acid and extract with ethyl ether. The organics are dried over anhydrous magnesium sulfate, filtered, and concentrated to yield 26.72 g (52%) of the desired product. mp237−
239℃. analysis. _{Calculated values for C11H8O4N1F5} : C42.17; _H2.55 ; N4.47. Actual value: C43.29; H2.81; N4.34. In a similar manner to Examples 39 and 40, other asymmetric pyridine dicarboxylic acids of the invention are made as shown in Table 7 utilizing the starting materials listed therein. TABLE The mono- and di-acid chlorides of the present invention represented by the formulas and are made from the corresponding mono- and di-acids, as illustrated by Examples 44-51 below. Example 44 Preparation of ethyl 5-chlorocarbonyl-6-(difluoromethyl)-4-isopropyl-2-(trifluoromethyl)-pyridine-3-carboxylate 3.72 g (0.105 mol) of the product of Example 31 and 50 ml of chloride The mixture with thionyl is kept at reflux for 18 hours and then concentrated under reduced pressure to give 3.9 g (97%) of the desired product as an oil, n ²⁵ _D 1.4570. analysis. _Calculated values _{for C14H13Cl1F5NO3} : C45.00; _H3.51 ; _N3.75 . Actual value: C45.10; H3.53; N3.68. In a manner similar to Example 44, other mono- and di-acid chlorides of the invention were made from the starting materials shown in Table 8 and are listed in Table 8. [Table] [Table] Example 52 Preparation of 3-ethyl 5-methyl-6-(difluoromethyl)-4-propyl-2-(trifluoromethyl)-3,5-pyridinedicarboxylate Product of Example 47 5.0 A mixture of g and 100 ml of methanol is kept at reflux for 18 hours and then concentrated. Dissolve the residue in ether. The ethereal solution is washed with aqueous saturated sodium bicarbonate, dried, and concentrated to give 2.37 g (48%) of the desired product as an oil.
n ²⁵ _D 1.4428. analysis. _Calculated values _{for C15H16F5N1O4} : C48.92; _H4.11 ; _N3.80 . Actual value: C49.00; H4.13; N3.76. Example 53 3-ethyl5-methyl6-(difluoromethyl)
- Preparation of 4-isopropyl-2-(trifluoromethyl)-3,5-pyridinedicarboxylate A mixture of 2.8 g (0.0074 mol) of the product of Example 44 and 60 ml of methanol is kept at reflux for 3 hours and then concentrated. to give 1.61 g (59%) of the desired product as an oil, n ²⁵ _D 1.4483. analysis. _{Calculated values for C15H16F5N1O4} : C48.79; _H4.37 ; N3.79. Actual value: C48.69; H4.41; N3.75. Example 54 Preparation of 3-methyl-5-ethyl-2-(difluoromethyl)-4-isobutyl-6-(trifluoromethyl)-3,5-pyridinedicarboxylate 10 g (0.0270 mol) of the product of Example 32 and A mixture of 100 ml of thionyl chloride is kept at reflux overnight and then concentrated to give a residue (9.59 g). A portion of this residue (5.03 g) is kept at reflux with 50 ml of methanol for 3 hours and then concentrated. This remainder (3.72
g) is subjected to Kugelrohr distillation to obtain the desired product.
Giving 2.83g (56.3%) as oil, n ²⁵ _D 1.4453. analysis. _Calculated values _{for C16H18F5N1O4} : C50.13; _H4.73 ; _N3.65 . Actual value: C49.91; H4.87; N3.43. Example 55 3-ethyl5-methyl-4-cyclopropyl-
Preparation of 6-(difluoromethyl)-2-(trifluoromethyl)-3,5-pyridinedicarboxylate 3.0 g (0.008 mol) of the product of Example 50 and methanol
The mixture with 30 ml is kept at reflux for 1.5 hours and then concentrated. The residue (2.81 g) is recrystallized from petroleum ether to give 1.85 g (63.1%) of the desired product as white crystals, mp 61-63°C. analysis. _{Calculated values for C15H14F5N1O4} : C49.05; _H3.84 ; N3.81. Actual value: C48.99; H3.88; N3.79. A second crop (0.69 g, 23.5%) is also isolated from the mother liquor, mp 49-52°C. Example 56 Preparation of dimethyl-2,6-bis(trifluoromethyl)-4-ethyl-3,5-pyrimidinedicarboxylate 5 g (0.0136 mol) of the product of Example 48 are added to 70 ml of methanol in a 500 ml flask. Heat the reaction mixture to reflux and reflux for 9 hours. The mixture was concentrated, diluted with ethyl ether, washed with aqueous saturated sodium bicarbonate solution, and anhydrous _MgSO4
and concentrated to give 3.3 g (68%) of the desired product.
obtained, mp45−47℃. analysis. _Calculated values for _C13H11O4N1F6 : _C43.45 ; _H3.06 ; _N3.89 . Actual value: C43.57; H3.06; N3.86. Other compounds of the invention are made in a similar manner to the procedures of Examples 52-56 above. As discussed above with respect to Table 4, additional examples are set forth in Table 9 below, taking into account the reaction conditions appropriate to the starting materials used in turn and the reactants used. [Table] Ruboxylate

[Table] Dicarboxylate

Example 69 3-ethyl 5-methyl 2-(difluoromethyl)
-4-isobutyl-6-(trifluoromethyl)
- Preparation of 3,5-pyridinecarboxylate 2.9 g (0.00817 mol) of the product of Example 30, 11 g (0.0705 mol) of ethyl iodide, 1.3 g of potassium carbonate
(0.00942 mol) and 50 ml of acetone.
Hold at reflux for an hour and then concentrate. water the residue
Treat with 200 ml and extract twice with 50 ml of ether.
The ether extract was washed once with 50 ml of sodium bicarbonate, then dried (MgSO ₄ ) and concentrated to give an oil, which was added to 2 Torr (pot temperature 130°C).
The desired product is subjected to Kugelrohr distillation with
Giving 3.0g (98%) as liquid, n ²⁵ _D 1.4469. analysis. _Calculated values _{for C16H18F5N1O4} : C50.13; _H4.73 ; _N3.65 . Actual value: C50.19; H4.78; N3.56. Other pyridine dicarboxylates of the invention are made in a manner similar to the procedure of Example 69. Starting materials used instead, as described above for Table 4,
Further examples are provided as shown in Table 10, taking into account the reaction conditions appropriate to the reactants used as well as the reactants used. [Table] Dicarboxylate


73 Example 43 _{K2CO3 -} DMF-room temperature
Dipropargyl 2-(difluoromethyl)-4-y
BrCH ₂ C≡CH
Sobutyl-6-(trifluoromethyl)-3,5-


(
pyridine dicarboxylate)


74 Example 42 K ₂ CO ₃ - Acetone - Reflux
Dimethyl 2-(difluoromethyl)-4-(methoxy
CH ₃ I
dimethyl)-6-(trifluoromethyl)-3,5-


Pyridine dicarboxylate


[Table] Example 75 Production of 3-methyl 5-ethyl 2-(difluoromethyl)-4-(1-ethylpropyl)-6-(trifluoromethyl)-3,5-pyridinedicarboxylate 90% of Example 22 12.0 g (0.0386 mol) of purity product,
A mixture of 2.6 g (0.0394 mol) of 85% potassium hydroxide, 30 ml of ethanol and 2 ml of water is held at reflux for 20 hours and then concentrated. Treat the residue with 100 ml of water and then extract with 100 ml of ether. The aqueous layer is acidified with 50 ml of concentrated HCl. The oily precipitate is extracted with 200 ml of ether. The ether solution is dried (MgSO ₄ ) and concentrated to give 10.8 g of syrup.
A portion (8.8 g) of this syrup was added to 34 ml of methyl iodide.
g, K ₂ CO ₃ 3.16 g (0.0230 mol) and acetone
Mix with 30ml. The mixture was stirred and held at reflux for 3 hours and then concentrated. Stir the residue with 100 ml of ether and 100 ml of water. The ether solution is washed once with saturated NaHCO ₃ and concentrated to give 7.6 g of a brown oil, which is subjected to Kugelrohr distillation at 1.5 torr (pot temperature 115° C.) to give 7.6 g.
gives the distillate of This distillate is chromatographed on silica gel by HPLC using 3% ethyl acetate-cyclohexane as eluent. 1st fraction (residence time 14-16 minutes)
is 2 g of a mixture of desired product and unidentified material. The second fraction is 4.3g of oil, 1
After Kugelrohr distillation at Torr (pot temperature 130° C.), 4.1 g of the desired product are given as a colorless oil, n ²⁵ _D 1.4519. Analysis _{Calculated for C17H20F5NO4} : C, 51.39; _H , 5.07; N, 3.53. Actual values: C, 51.40; H, 5.14; N, 3.50. Other pyridine carboxylic acid monoesters of the invention listed in Table 11 are made by a method similar to that described for Example 30. [Table] Ester

Example 80 Preparation of 3-methyl 5-propargyl 2-(difluoromethyl)-4-isobutyl-6-(trifluoromethyl)-3,5-pyridinedicarboxylate 2.1 g of the product of Example 79, 1.1 g of potassium carbonate, A mixture of 25.3 g methyl iodide and 40 ml DMF is stirred for 24 hours and then poured into water. This mixture is extracted with ether. ether extract with 100ml of water
Wash twice, dry and concentrate. The residue was subjected to Kugelrohr distillation at 0.5 Torr to give 2.1 g of the desired product.
(96%) given as oil, n ²⁵ _D 1.4598. Analysis _{Calculated for C17H16F5N1O4} : C, _51.91 ; _H , 4.10; N, 3.56. Actual values: C, 51.92; H, 4.14; N, 3.56. Example 81 Preparation of 3-methyl 5-methyl 2-(difluoromethyl)-4-(methoxymethyl)-6-(trifluoromethyl)-3,5-pyridinedicarboxylate Follow the procedure of Example 69 except that the starting materials 3-Ethyl 5-methyl-2-(difluoromethyl)-4-(methoxymethyl)-6-(trifluoromethyl)-3,5-pyridinedicarboxylate is an oil, except that it is the product of Example 78. , n ²⁵ _D 1.4467. Analysis _{Calculated for C14H14F5N1O5} : C, 45.29; _H , 3.80; _N , 3.77. Actual values: C, 45.39; H, 3.84; N, 3.74. Other 5-chlorocarbonyl-3-pyridine carboxylates of the invention were prepared from the corresponding 3,5-pyridinedicarboxylic acid 3-monoesters by a method similar to that described in Example 44 and were
It's being held up. [Table] Pyridine carboxylate

Other unsymmetrical pyridine dicarboxylates of the present invention are prepared from the corresponding 5-chlorocarbonyl-3-pyridine carboxylates and appropriate alcohols by a method similar to that described in Example 52 and are listed in Table 13. ing. [Table] Example 87 Preparation of 3-ethyl 5-methyl 2,6-bis(difluoromethyl)-4-propyl-3,5-pyridinedicarboxylate 5.67 g (0.016 mol) of the product of Example 11, 85%
A mixture of 1.06 g (0.016 mol) KOH, 40 ml ethanol and 10 ml water is stirred for 24 hours and then concentrated. Treat the residue with 50 ml of water, then 50 ml of ether.
Extract with The aqueous layer is acidified with 50 ml of concentrated HCl.
The oily precipitate was extracted with ether and dried (MgSO ₄ ).
and concentrated to give 2.64 g (49%) of the monoacid. A portion of this acid (1.64 g, 0.0048 mole) is refluxed with thionyl chloride until HCl evolution ceases. The reaction mixture is concentrated, then the residue is dissolved in ether, dried over MgSO ₄ and then concentrated to give 1.22 g of the desired product as an oil, n ²⁵ _D 1.4629. Analysis _{Calculated for C15H17F4NO4} : C, 51.29; _H , 4.88; N, 3.99. Actual values: C, 50.93; H, 4.99; N, 3.87. Example 88 Preparation of ethyl 5-(aminocarbonyl)-6-(difluoromethyl)-4-ethyl-2-trifluoromethyl)-3-pyridinecarboxylate.
Dry ice, acetone,
Condense using a condenser. ether 50
7 g (0.0196 mol) of the product of Example 46 are added to ml. This ethereal solution is slowly poured into the reaction flask and the whole mixture is then stirred for 18 hours. The resulting solid is washed with water and dried under reduced pressure for 18 hours to give 5.67 g (86%) of the desired product, mp165−167
℃. Analysis _{Calculated for C13H13O3N2F5} : C, 45.88; _H , 3.82; N, _8.23 . Actual values: C, 45.87; H, 3.84; N, 8.23. In a manner similar to Example 88, other pyrimidine carboxamides of the invention are made as shown in Table 14. [Table] Boxylate

Example 92 Ethyl 5-cyano-6-(difluoromethyl)
-4-ethyl-2-(trifluoromethyl)-3
- Preparation of pyridine carboxylate 3.5 g (0.0102 mol) of the product of Example 88 are added to 100 ml of phosphorous oxychloride in a 500 ml flask. The mixture is refluxed for 18 hours, concentrated, washed with water and extracted with ethyl ether. Anhydrous ether extract
Dry over _MgSO4 , concentrate and further dry under reduced pressure to obtain 1.23 g (37%) of the desired product, m.
p.38−40℃. Analysis Calculated for C ₁₃ H ₁₁ O ₂ N ₂ F ₅ : C, 48.44; H, 3.41; N, 8.69. Actual values: C, 48.38; H, 3.48; N, 8.65. Example 93 Ethyl 5-cyano-6-(difluoromethyl)-
4-n-propyl-2-(trifluoromethyl)
Preparation of -3-pyridinecarboxylate 4.0 g (0.0112 mol) of the product of Example 91 and 100 g of phosphorus oxychloride are held at reflux for 20 hours and then concentrated. Pour the residue into water and extract with ether.
The ether extract is dried (MgSO ₄ ) and concentrated. Kugelrohr distillation of the residue at 0.1 Torr gave 2.26 g of oil, which was recrystallized from hexane at low temperature to give 1.11 g of the desired product as a solid, mp 40-41°C. Analysis _{Calculated for C14H13F5N2O2} : C, 50.01; H, 3.90; _N , _8.33 . Actual values: C, 49.75; H, 3.98; N, 8.21. Example 94 Diethyl 2,6-bis(trifluoromethyl)
-4-(1-methyl-3-butenyl)-3,5-
Preparation of Pyridine Dicarboxylate A 250 ml three-necked flask is dried and then purged with argon. Dry tetrahydrofuran approx.
ml into the flask through a dropper. The flask is cooled to -78°C, and 14 ml (0.0227 mol) of 1.6M n- butyllithium is added thereto, followed by 2.96 ml (0.0227 mol) of diisopropylamine. 5
After stirring for a minute, 8.8 g (0.0227 mol) of the product of Example 1
diluted with 10 ml of dry tetrahydrofuran, then
Inject into the above flask. This mixture is stirred for 1 hour. Allyl bromide (allyl) in this mixture 4.23
g (0.035 mol) is added and the mixture is then stirred for 90 minutes at room temperature. The mixture is diluted with ethyl ether and then washed successively with water and 10% aqueous HCl. Dry the organics over MgSO ₄ and concentrate. Chromatography in 5% ethyl acetate/cyclohexane yields 1.4 g (14.4%) of the desired product.
n ²⁵ _D 1.4410. Analysis Calculated for C ₁₈ H ₁₉ O ₄ N ₁ F ₆ : C, 50.58; H, 4.44; N, 3.27. Actual values: C, 50.69; H, 4.47; N, 3.30. Example 95 Diethyl 2,6-bis(trifluoromethyl)
Production of -4-(3-butenyl)-3,5-pyridinedicarboxylate After heating and drying a 250 ml three-necked flask,
Purge with argon. Tetrahydrofuran (50
ml) through a dropper and then cool the flask to -78°C. With this and a dropper
1.6M n -butyllithium 8.33ml (0.0133mol)
and then 2 ml (0.0133 mol) of diisopropylamine are added. 10ml dry tetrahydrofuran
5 g (0.0133 mol) of the product of Example 2 are added to
This solution is then injected into the reaction mixture. This mixture is stirred for 1 hour. Allyl bromide 2.4g
(0.02 mol) is injected into the flask and the mixture is stirred at room temperature for 90 minutes. Dilute this mixture with ethyl ether and then
Continue washing with water and 10% HCl. The organics were dried, concentrated and then chromatographed with 5% ethyl acetate in cyclohexane to give 0.7 g (29.26%) of the product, n ²⁵ _D 1.4365. Analysis Calculated for C ₁₇ H ₁₇ O ₄ N ₁ F ₆ : C, 49.39; H, 4.11; N, 3.39. Actual values: C, 49.54; H, 4.14; N, 3.36. Example 96 Ethyl 6-(difluoromethyl)-4-ethyl-
Preparation of 5-hydroxymethyl-2-(trifluoromethyl)-3-pyridinecarboxylate Place the product of Example 28 in a dry 500 ml four-necked flask.
30.6g (0.09mol) and tetrahydrofuran 40
ml under nitrogen. The reaction mixture was incubated in an ice water bath for 10 min.
Cool to ℃. 180 ml of 1M borane in tetrahydrofuran is added to the solution via a dropper. The reaction mixture is stirred for 160 hours and poured into water. The organics are extracted into 300 ml of ether and the ether extract is then washed with 200 ml of saturated sodium bicarbonate, dried (MgSO ₄ ) and concentrated. The residue is crystallized from petroleum ether to give 25 g (84.9%) of the desired product, mp 59.5
−60.5℃. Analysis _{Calculated for C13H14F5N1O3} : C, _47.71 ; H, 4.31; N, _4.28 . Actual values: C, 47.72; H, 4.31; N, 4.25. Example 97 Ethyl 6-(difluoromethyl)-4-ethyl-
5-formyl-2-(trifluoromethyl)-3
- Preparation of pyridine carboxylate 4.74 g (0.0145 mol) of the product of Example 96, 8.6 g (0.0336 mol) of pyridinium chlorochromate and 70 ml of CH ₂ Cl ₂ are kept at room temperature for 18 hours. this
The CH ₂ Cl ₂ solution is decanted and then chromatographed on silica gel using CH ₂ Cl ₂ as eluent. The first two eluates yielded 3.93 g of desired product.
(83.4%) as a white solid, mp63.5−65
℃. Example 98 Diethyl 2-(difluoromethyl)-4-(2-
Preparation of methylsulfonylethyl)-6-(trifluoromethyl)-3,5-pyridinedicarboxylate 12.0 g of the product of Example 23 in 200 ml of methylene chloride
m-chloroperbenzoic acid in a solution of (0.0289 mol)
Add 13.0g (0.064 mol). reaction mixture
Stir for 24 hours and then pour into a mixture of 25 ml of 10% sodium hydroxide and 400 ml of water. The methylene chloride layer is separated, washed sequentially with diluted sodium bicarbonate, sodium thiosulfate, saturated sodium chloride, dried, and concentrated to give 12.9 g of a solid.
A portion (5.0 g) of this solid was eluted using 33% ethyl acetate/cyclohexane.
Purification by HPLC gives 3.6 g of the desired product, mp 98-101°C. Analysis Calculated for C ₁₆ H ₁₈ F ₅ N ₁ O ₆ S: C, 42.96; H, 4.06; N, 3.13. Actual values: C, 42.80; H, 4.06; N, 3.12. Example 99 Preparation of 3-ethyl 5-methyl 6-(difluoromethyl)-4-vinyl-2-(trifluoromethyl)-3,5-pyridinedicarboxylate 17.31 g (0.0387 mol) of the product of Example 98, water A mixture of 2.16 g (0.054 mol) sodium oxide, 125 ml water and 60 ml ethanol is stirred for 24 hours and then concentrated. The residue is stirred with ether and 600 ml of 1.5N sodium hydroxide. The aqueous layer is acidified with concentrated hydrochloric acid. Organic matter is methylene chloride (2×
400ml). The methylene chloride extract was dried and concentrated to give 11.67 g of residue. This residue, 14.70 g (0.104 mol) methylene chloride,
14.3g (0.104mol) potassium carbonate and 300ml
The acetone mixture is refluxed for 18 hours and then concentrated. Stir the residue with 500 ml of water and 500 ml of ether. Dry the ether layer and concentrate. The residue is subjected to Kugelrohr distillation at 0.3 Torr to give 7.50 g (62%) of the desired product, n ²⁵ _D 1.4567. Analysis _{Calculated for C14H12F5N1O4} : C, 47.60; _H , 3.42; _N , 3.97. Actual values: C, 47.46; H, 3.55; N, 3.85. Example 100 Preparation of diethyl 4-[2-(methylsulfinyl)-ethyl]-2-(difluoromethyl)-6-(trifluoromethyl)-pyridine-3,5-dicarboxylate 50 ml cooled in a water bath To a stirred solution of 20.09 g (0.048 mol) of the product of Example 23 in methylene was added 10.3 g of m -chloroperbenzoic acid in 100 ml of methylene chloride.
(0.050 mol) is added while keeping the reaction temperature below 10°C. Stirring and ice bath cooling are continued for 1 hour after addition is complete. Add 25 ml of 10% sodium hydroxide to the resulting slurry.
and 600 ml of water. After mixing well, the phases separate. The aqueous phase is extracted with 50 ml of methylene chloride. Combine each methylene chloride phase and add 600 ml of 0.5% sodium bicarbonate solution;
Washing successively with 0.5% sodium chloride solution, drying over magnesium sulfate, filtering and stripping gives 20.5 g of a pale yellow solid. This product was recrystallized twice from hexane/ether to give 12.5 g of a white solid, mp90.5-
91.5℃, yield 60%. Analysis Calculated for C ₁₆ H ₁₈ F ₅ N ₁ O ₅ S ₁ : C, 44.55; H, 4.21; N, 3.25. Actual values: C, 44.45; H, 4.22; N, 3.20. Example 101 Preparation of 3-ethyl 5-methyl 6-(difluoromethyl)-4-(methylthiomethyl)-2-(trifluoromethyl)-3,5-pyridinedicarboxylate 32.8 g of the crude product of Example 25 (0.081 mol), 37 g of 10% sodium hydroxide, 35 ml of water and 125 ml of ethanol
ml of the mixture is stirred for 1 hour and then concentrated. The residue is stirred with 700 ml of water and 200 ml of methylene chloride. The aqueous layer is made acidic and the precipitate is extracted into methylene chloride. Dry and concentrate this methylene chloride extract to give 19.9 g of acid, mp81-85
℃. Part of this acid (10.6 g, 0.1078 mol), 5.2 ml (0.085 mol) of methyl iodide, 11.8 g of potassium carbonate
(0.085 mol) and 150 ml of acetone, 24
Hold at reflux for an hour. The reaction mixture is concentrated and the residue is stirred with 150 ml of methylene chloride and 200 ml of water. The methylene chloride layer is dried and concentrated. The residue is subjected to Kugelrohr distillation at 0.25 torr (pot temperature 135-170°C) to give 7.16 g of distillate. This distillate was converted into 7% ethyl acetate/
Purify by HPLC using cyclohexane as eluent. Initial fraction (residence time 4-6 minutes) is 4.75
g of a solid, which is recrystallized twice from hexane/ether to give 2.78 g of the desired product. mp67−68.5℃. Analysis Calculated for C ₁₄ H ₁₄ F ₅ N ₁ O ₄ S ₁ : C, 43.41; H, 3.64; N, 3.62. Actual values: C, 43.13; H, 3.61; N, 3.55. Example 102 Preparation of diethyl 6-(difluoromethyl)-2-(trifluoromethyl)-4-vinyl-3,5-pyridinedicarboxylate 3.7 g of the product of Example 99, 10% sodium hydroxide
A mixture of 13.75 g and 100 ml of water is stirred for 24 hours and then concentrated. Residue 300ml water and 50ml
Stir with ml of methylene chloride. The methylene chloride extract is dried and concentrated to give 2.99 g of a yellow solid, which is recrystallized from petroleum ether to give 2.01 g of a white solid. This solid, 1 ml of ethyl iodide,
A mixture of 10ml DMF and 2.09g potassium carbonate
Stir for 24 hours, then pour into 300ml of water. The reaction mixture is extracted with methylene chloride and the methylene chloride extract is dried and concentrated. The residue is subjected to Kugelrohr distillation at 0.1 Torr to give 1.41 g of the desired product, n ²⁵ _D 1.4529. Analysis _{Calculated for C15H14F5N1O4} : C, _49.05 ; H, 3.84; _N , 3.81. Actual values: C, 49.09; H, 3.84; N, 3.81. Example 103 Preparation of diethyl 4-[(1-ethoxy)methoxymethyl]-2-(difluoromethyl)-6-(trifluoromethyl)-pyridine-3,5-dicarboxylate 4.0 g of the product of Example 24 (0.010 mole) of carbon tetrachloride
Add 2.5 g (0.015 mol) of bromine to the stirred solution in 30 ml. The solution is cooled to 10°C, a stream of dry nitrogen is passed over the reaction mixture (to purge the hydrogen bromide), and the reaction is illuminated by a 150 watt spotlight. The reaction temperature was 10-15℃.
Keep time. Remove light and stop nitrogen flow. 1.41 g (0.013 mol) of 2, in 5 ml of absolute ethanol
adding a solution of 6-lutidine to the reaction mixture;
The resulting reaction mixture is stirred for 18 hours at ambient temperature. Add 100 ml of the reaction mixture with 50 ml of methylene chloride.
pour into the water. After stirring well, separate the organic phase,
Washed with 100 ml of 0.50% hydrochloric acid solution and 100 ml of 1% sodium bicarbonate, dried over magnesium sulfate,
Filter and then strip to give 4.29 g of a yellow oil. This product was purified on silica gel using 10% ethyl acetate in cyclohexane as solvent.
Purification by HPLC gives 2.18 g of pale yellow oil, yield 48%, n ²⁵ _D 1.4446. Analysis _Calculated for _C17H20F5N1O6 : C, _47.56 ; _H , 4.70; _N , 3.26. Actual values: C, 47.55; H, 4.71; N, 3.26. In a similar manner to the procedure of Example 103, the product of Example 24 is brominated and the resulting product is then reacted with a suitable alcohol or alkylthiol as shown in the following examples listed in Table 15. Provides the listed product. [Table] Xylate

In a similar manner to Example 39, further pyridine dicarboxylic acids of the invention are made as shown in Table 16. [Table] [Table] Example number Departure
Former
No. Compound Substance
Empirical formula mp℃ element Calculated value Actual value

Claims (1)

[Claims] 1. Structural formula [Wherein, R is lower alkyl, lower alkenyl, lower alkynyl, lower alkenylalkyl, haloalkyl, haloalkenyl, C _3-7 cycloalkyl,
C _3-6 cycloalkanylalkyl, aryl, arylmethyl, alkoxyalkyl, benzyloxymethyl, alkylthioalkyl, dialkoxyalkyl, (1-alkoxy-1-alkylthio)
Alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylsulfonylalkyl, alkylsulfinylalkyl, alkyl substituted with dialkylsulfonium salts, cyanoalkyl, carbamylalkyl, carboalkoxyalkyl, carbalkoxyalkenyl, formalyl Saturated and unsaturated heterocyclic groups selected from the group consisting of alkyl, dialkylaminoalkenyl, and furyl, pyridyl, thienyl, thiiranyl, oxiranyl, and aziridinyl, which group is attached to the pyridine ring by a C-C bond. , and lower alkyl substituted with a saturated or unsaturated heterocyclic group selected from the group consisting of furyl, pyridyl, thienyl, thiiranyl, oxiranyl and aziridinyl; R ₁ and R ₂ are alkyl and fluorinated methyl independently selected from, provided that one of R ₁ and R ₂ is fluorinated methyl; and X or Y is {where Z ₁ is O and NR ₇ (R ₇ is selected from hydrogen and lower alkyl), and Z ₂ is O and S
and R ₃ in each case is independently selected from hydrogen, C _1-4 alkyl, C _3-4 alkenylalkyl, C _1-4 haloalkyl, cyanoalkyl, cycloalkanylalkyl, C _3-4 alkynylalkyl but when Z ₂ is S in both cases
R ₃ shall be C _1-2 lower alkyl}, (wherein R ₄ is selected from hydrogen and halogen), and (wherein R ₅ and R ₆ are independently selected from hydrogen, lower alkyl and phenyl); -CH ₂ OH; and -C≡N)]
A compound represented by 2. The compound according to claim 1, wherein one of R ₁ and R ₂ is a trifluoromethyl group and the other is a fluorinated methyl group. 3 X and Y are 3. The compound according to claim 2. 4. A compound according to claim 3, wherein 4R is selected from lower alkyl, lower alkenyl, lower alkenylalkyl, lower alkynyl, _C3-7 cycloalkyl, haloalkyl, and _C3-6 cycloalkanylalkyl. 4. A compound according to claim 3, wherein 5R is selected from alkoxyalkyl, benzyloxymethyl, dialkoxyalkyl, alkylthioalkyl, (1-alkoxy-1-alkylthio)alkyl, and dialkylaminoalkyl. 6. The compound according to claim 2, wherein one of X and Y is [Formula] and the other is -C≡N. 7. A compound according to claim 6, wherein 7R is selected from lower alkyl, lower alkenyl, lower alkenylalkyl, lower alkynyl, _C3-7 cycloalkyl, haloalkyl, and _C3-6 cycloalkanylalkyl. 7. A compound according to claim 6, wherein 8R is selected from alkoxyalkyl, benzyloxymethyl, dialkoxyalkyl, alkylthioalkyl, (1-alkoxy-1-alkylthio)alkyl, and dialkylaminoalkyl. 9. The compound according to claim 1, wherein one of R ₁ and R ₂ is a trifluoromethyl group and the other is an alkyl group. 10 X and Y are 10. The compound according to claim 9. 11. A compound according to claim 10, wherein 11R is selected from lower alkyl, lower alkenyl, lower alkenylalkyl, lower alkynyl, _C3-7 cycloalkyl, haloalkyl, and _C3-6 cycloalkanylalkyl. 12 R is alkoxyalkyl, benzyloxymethyl, dialkoxyalkyl, alkylthioalkyl, (1-alkoxy-1-alkylthio)
11. A compound according to claim 10, selected from alkyl, and dialkylaminoalkyl. 13 X or Y is and the other is -C≡N. 14. A compound according to claim 13, wherein 14R is selected from lower alkyl, lower alkenyl, lower alkenylalkyl, lower alkynyl, _C3-7 cycloalkyl, haloalkyl, and _C3-6 cycloalkanylalkyl. 15 R is alkoxyalkyl, benzyloxymethyl, dialkoxyalkyl, alkylthioalkyl, (1-alkoxy-1-alkylthio)
14. A compound according to claim 13 selected from alkyl, and dialkylaminoalkyl. 16 R ₁ is trifluoromethyl, R ₂ is selected from methyl, monofluoromethyl, and difluoromethyl, R is selected from isopropyl, cyclopropylmethyl, isobutyl, propyl, and X and Y are 2. A compound according to claim 1, wherein _Z2 is O or S and _R3 is methyl or ethyl. 17 R ₁ is trifluoromethyl, R ₂ difluoromethyl, R is methylthiomethyl, and X and Y are 2. A compound according to claim 1, wherein _R3 at each occurrence is independently methyl or ethyl. 18 Auxiliary agents and structural formula [Wherein, R is lower alkyl, lower alkenyl, lower alkynyl, lower alkenylalkyl, haloalkyl, haloalkenyl, C _3-7 cycloalkyl,
C _3-6 cycloalkanylalkyl, aryl, arylmethyl, alkoxyalkyl, benzyloxymethyl, alkylthioalkyl, dialkoxyalkyl, (1-alkoxy-1-alkylthio)
Alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylsulfonylalkyl, alkylsulfinylalkyl, alkyl substituted with dialkylsulfonium salts, cyanoalkyl, carbamylalkyl, carboalkoxyalkyl, carbalkoxyalkenyl, formalyl Saturated and unsaturated heterocyclic groups selected from the group consisting of alkyl, dialkylaminoalkenyl, and furyl, pyridyl, thienyl, thiiranyl, oxiranyl, and aziridinyl, which group is attached to the pyridine ring by a C-C bond. , and lower alkyl substituted with a saturated or unsaturated heterocyclic group selected from the group consisting of furyl, pyridyl, thienyl, thiiranyl, oxiranyl and aziridinyl; R ₁ and R ₂ alkyl and fluorinated methyl. independently selected, provided that one of R ₁ and R ₂ is fluorinated methyl; and X and Y are {where Z ₁ is O and NR ₇ (R ₇ is selected from hydrogen and lower alkyl), and Z ₂ is O and S
and R ₃ in each case is independently selected from hydrogen, C _1-4 alkyl, C _3-4 alkenylalkyl, C _1-4 haloalkyl, cyanoalkyl, cycloalkanylalkyl, C _3-4 alkynylalkyl but when Z ₂ is S in both cases
R ₃ shall be C _1-2 lower alkyl}, and (wherein R ₅ and R ₆ are independently selected from the group consisting of hydrogen, lower alkyl and phenyl; -CH ₂ OH; and -C≡N)]
A herbicide containing a compound represented by. 19. The composition of claim 18, wherein one of _R1 and _R2 is a trifluoromethyl group and the other is a fluorinated methyl group. 20 X and Y are 20. The composition according to claim 19. 21. The composition of claim 20, wherein 21R is selected from lower alkyl, lower alkenyl, lower alkenylalkyl, lower alkynyl, _C3-7 cycloalkyl, haloalkyl, and _C3-6 cycloalkanylalkyl. 22 R is alkoxyalkyl, benzyloxymethyl, dialkoxyalkyl, alkylthioalkyl, (1-alkoxy-1-alkylthio)
21. A composition according to claim 20, selected from alkyl, and dialkylaminoalkyl. 23 One of X and Y is and the other is -C≡N.
The composition described in. 24. The composition of claim 23, wherein 24R is selected from lower alkyl, lower alkenyl, lower alkenylalkyl, lower alkynyl, _C3-7 cycloalkyl, haloalkyl, and _C3-6 cycloalkanylalkyl. 25 R is alkoxyalkyl, benzyloxymethyl, dialkoxyalkyl, alkylthioalkyl, (1-alkoxy-1-alkylthio)
24. The composition of claim 23, selected from alkyl, and dialkylaminoalkyl. 26. The composition of claim 18, wherein one of R ₁ and R ₂ is a trifluoromethyl group and the other is an alkyl group. 27 X and Y are 27. The composition of claim 26. 28. The composition of claim 27, wherein 28R is selected from lower alkyl, lower alkenyl, lower alkenylalkyl, lower alkynyl, _C3-7 cycloalkyl, and _C3-6 cycloalkanylalkyl. 29 R is alkoxyalkyl, benzyloxymethyl, dialkoxyalkyl, alkylthioalkyl, (1-alkoxy-1-alkylthio)
28. The composition of claim 27, selected from alkyl, and dialkylaminoalkyl. 30 One of X and Y is and the other is -C≡N.
The composition described in. 31. The composition of claim 30, wherein 31R is selected from lower alkyl, lower alkenyl, lower alkenylalkyl, lower alkynyl, _C3-7 cycloalkyl, and _C3-6 cycloalkanylalkyl. 32 R is alkoxyalkyl, benzyloxymethyl, dialkoxyalkyl, alkylthioalkyl, (1-alkoxy-1-alkylthio)
31. The composition of claim 30, selected from alkyl, and dialkylaminoalkyl. 33 R ₁ is trifluoromethyl, R ₂ is selected from methyl, monofluoromethyl, and difluoromethyl, R is selected from isopropyl, cyclopropylmethyl, propyl, isobutyl, and X and Y are 19. The composition of claim 18, wherein _Z2 is O or S and _R3 is methyl or ethyl. 34 R ₁ is trifluoromethyl, R ₂ is difluoromethyl, R is methylthiomethyl, and X and Y are 19. The composition of claim 18, wherein in each case _R3 is independently methyl or ethyl. 35 Structural formula [Wherein, R is lower alkyl, lower alkenyl, lower alkynyl, lower alkenylalkyl, haloalkyl, haloalkenyl, C _3-7 cycloalkyl,
C _3-6 cycloalkanylalkyl, aryl, arylmethyl, alkoxyalkyl, benzyloxymethyl, alkylthioalkyl, dialkoxyalkyl, (1-alkoxy-1-alkylthio)
Alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylsulfonylalkyl, alkylsulfinylalkyl, alkyl substituted with dialkylsulfonium salts, cyanoalkyl, carbamylalkyl, carboalkoxyalkyl, carbalkoxyalkenyl and furyl, pyridyl , thienyl, thienyl, oxiranyl and aziridinyl, the group being attached to the pyridine ring by a C-C bond, and furyl, pyridyl, thienyl, thiranyl, oxiridinyl. and aziridinyl; R ₁ is fluorinated methyl, and R ₂ is difluoromethyl, monofluoromethyl and alkyl groups; and X and Y are _{independently} selected from _{the group consisting of} A method for producing a compound represented by the formula (wherein R, R ₁ , X and Y are the same groups as in the compound to be produced, and R′ ₂ is a group substituted with one more fluorine atom than R ₂ in the compound to be produced). reacting a starting compound, a contacting the starting material with an alkali metal borohydride in the presence of a first solvent to form a compound of the formula A method for producing the above-mentioned compound, which comprises: producing a dihydropyridine compound, and b contacting the dihydropyridine compound with a non-aqueous basic compound, optionally in the presence of a second solvent, to produce the target compound. 36. Claim 3, wherein the first solvent is N,N-dimethylformamide and the alkali metal borohydride is sodium borohydride.
The method described in 5. 37. The method of claim 35, wherein the second solvent is selected from diethyl ether and tetrahydrofuran. 38. A method according to claim 35, wherein the second solvent is selected from toluene or methylene chloride. 39 Non-aqueous organic bases include pyridine and mono-,
36. A method according to claim 35, selected from di- and tri-substituted pyridines. 40. The method of claim 35, wherein the non-aqueous organic base is selected from 1,8-diazabicyclo-[5.4.0]-undec-5-ene and trialkylamines. 41. The method of claim 36, wherein the second solvent is diethyl ether. 42 The second solvent is tetrahydrofuran,
37. The method of claim 36. 43. The method of claim 36, wherein the non-aqueous organic base is 2,6-lutidine. 44. The method of claim 36, wherein the non-aqueous organic base is 1,8-diazabicyclo-[5.4.0]-undec-5-ene. 45 Structural formula [Wherein, R is lower alkyl, lower alkenyl, lower alkynyl, lower alkenylalkyl, haloalkyl, haloalkenyl, C _3-7 cycloalkyl,
C _3-6 cycloalkanylalkyl, aryl, arylmethyl, alkoxyalkyl, benzyloxymethyl, alkylthioalkyl, dialkoxyalkyl, (1-alkoxy-1-alkylthio)
alkyl, dialkylaminoalkyl, alkylsulfonylalkyl, alkylsulfinylalkyl, and saturated and unsaturated heterocyclic groups selected from the group consisting of furyl, pyridyl, thienyl, thiiranyl, oxiranyl, and aziridinyl; R selected from the group consisting of lower alkyl substituted with a saturated or unsaturated heterocyclic group selected from the group consisting of furyl, pyridyl, thienyl, thiiranyl, oxiranyl and aziridyl, attached to the pyridine ring by a bond; ₂ is fluorinated alkyl, and R ₁ is selected from alkyl and fluorinated alkyl groups; and X and Y are (wherein R ₃ in each case is C _1-4 alkyl, C _3-4 alkenylalkyl, C _2-4 haloalkyl, or C _3-4
independently selected from the group consisting of 1,4-dihydropyridine of the formula 3,4-dihydropyridine (wherein R, R ₁ , X and Y are the same groups as in the target compound to be produced, and R′ ₂ is one more fluorine atom than the R ₂ group in the target compound to be produced) a substituted methyl group), contacting the dihydropyridine compound with a non-aqueous basic compound, optionally in the presence of a solvent, at elevated temperature to form the desired product compound. A method for producing the above compound, characterized in that: 46. A method according to claim 45, wherein the solvent is selected from tetrahydrofuran and toluene. 47 The non-aqueous organic base is selected from 1,8-diazabicyclo-[5.4.0]-undec-5-ene,
46. The method of claim 45. 48. The method of claim 45, wherein the non-aqueous organic base is selected from trialkylamines. 49. The method of claim 48, wherein the non-aqueous organic base is selected from tributylamine and triethylamine. 50 Non-aqueous organic bases include pyridine and mono-,
46. The method of claim 45, selected from di- and tri-alkyl substituted pyridines. 51. The method of claim 50, wherein the non-aqueous organic base is 2,6-lutidine. 52. The method of claim 45, wherein the non-aqueous organic base is selected from a mixture of 2,6-lutidine and a catalytic amount of 2,8-diazabicyclo-[5.4.0]-undec-5-ene. 53. Claim 4, wherein the contacting is carried out under reflux conditions.
The method described in 7. 54 Structural formula [Wherein, R is lower alkyl, lower alkenyl, lower alkynyl, lower alkenylalkyl, haloalkyl, haloalkenyl, C _3-7 cycloalkyl,
C _3-6 cycloalkanylalkyl, aryl, arylmethyl, alkoxyalkyl, benzyloxymethyl, alkylthioalkyl, dialkoxyalkyl, (1-alkoxy-1-alkylthio)
The group consisting of alkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylsulfonylalkyl, alkylsulfinylalkyl, alkyl substituted with dialkylsulfonium salts, cyanoalkyl, and furyl, pyridyl, thienyl, thiiranyl, oxiranyl, and aziridinyl. saturated and unsaturated heterocyclic groups selected from the group consisting of those attached to the pyridine ring by a C-C bond; selected from the group consisting of lower alkyl substituted with an unsaturated heterocyclic group; R ₂ is difluoromethyl and R ₁ is selected from methyl and trifluoromethyl; (wherein R ₃ is selected from C _1-4 alkyl, C _3-4 alkenylalkyl, C _2-4 haloalkyl, or C _3-4 alkynylalkyl), and Y is A compound with the structural formula [wherein R, R ₁ , R ₂ and X are the same groups as in the product compound, and Y' is of the formula wherein R′ ₃ is independently selected from C _1-4 alkyl, C _3-4 alkenylalkyl, C _2-4 haloalkyl, or C _3-4 alkynylalkyl) A process for the preparation of the above-mentioned compounds, characterized in that, in preparing the substances by hydrolysis, the starting material is brought into contact with at least one equivalent of water and one equivalent of an alkali metal hydroxide in a solvent. 55. The method of claim 54, wherein the solvent is an alcohol. 56. The method of claim 54, wherein the hydroxide is potassium hydroxide. 57. The method of claim 54, wherein the hydroxide is sodium hydroxide.