Title of Invention

METHOD FOR MANUFACTURING ARYL CARBOXAMIDES

Abstract Method for manufacturing aryl carboxamides of the formula (I), with Ar = singly to triply substituted phenyl, pyridyl or pyrazolyl rings, wherein the substituents are selected from halogen, C1-C4 alkyl and C1-C4 halogen alkyl; M = thienyl or phenyl, which can contain a halogen substituent; Q = direct bond, cyclopropylene, annulated bicyclo [2.2.1 ]heptane or bicyclo[2.2.1 ]heptene ring; R1 = hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 halogen alkoxy, singly to triply substituted phenyl, wherein the substituents are selected from halogen and trifluoromethylthio, or cyclopropyl; through reaction of an acid chloride of the formula (II) with an aryl amine (III) in a suitable nonaqueous solvent, wherein in the absence of an auxiliary base a) the acid chloride (II) is added, b) a pressure of 0 to 700 mbar is established, c) the aryl amine (III) is added in approximately stoichiometric amounts and d) the valuable product is isolated.
Full Text Method for manufacturing aryl carboxamides
Description
The present invention relates to a process for preparing arylcarboxamides of the
formula (I)

where the substituents are each defined as follows:
Ar is a mono- to trisubstituted phenyl, pyridyl or pyrazolyl ring, where the substituents
are each independently selected from halogen, C1-C4-alkyl and C1-C4-haloalkyl;
M is thienyl or phenyl, which may bear a halogen substituent;
Q is a direct bond, cyclopropylene, a fused bicyclo[2.2.1]heptane or
bicyclo[2.2.1]heptene ring;
R1 is hydrogen, halogen, C1-C6-alkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, mono- to
trisubstituted phenyl, where the substituents are each independently selected from
halogen and trifluoromethylthio, or cyclopropyl;
by reacting an acid chloride of the formula (II)

with an arylamine (III)

in a suitable nonaqueous solvent.
JP-A 2001/172276 discloses that alky!- or phenylcarbonyl chlorides can be reacted with
arylamines under reduced pressure. The reactions described are carried out without an
auxiliary base, but in highly dilute solutions. For an industrial scale preparation of the
arylcarboxamides (I), this process is, however, unsuitable owing to the large amounts
of solvent. A more concentrated mode of operation is not possible, since this leads to
lump formation and mixing problems, which greatly reduces the yield of product of
value.
Other processes described in the literature for preparing carboxamides from acid
chloride and arylamine without use of an auxiliary base (cf., for example, Journal of
Combinatorial Chemistry (2003), 5(3), 253-259, Structural Chemistry (2006), 17(2),
241-247 and JP-A 1973/049217) are not usable on the industrial scale, because they
afford the desired products of value only in poor yields.
It was accordingly an object of the present invention to provide a process usable on the
industrial scale for preparing the arylcarboxamides (I).
Accordingly, it has been found that the arylcarboxamides (I) are obtainable in high
yields by, in the absence of an auxiliary base,
a) initially charging the acid chloride (II),
b) establishing a pressure of from 0 to 700 mbar,
c) metering in the arylamine (III) in an approximately stoichiometric amount and
d) isolating the product of value.
The acid chlorides (II) are either commercially available or can be prepared, for
example, according to R. C. Larock, Comprehensive Organic Transformations, Verlage
Wiley-VCH, 2nd Edition 1999, pages 1929 ff.
The arylamines (III) are generally obtainable by hydrogenating the corresponding
nitroaromatics. Further details can be found, for example, in R. C. Larock,
Comprehensive Organic Transformations, Verlage Wiley-VCH, 2nd Edition 1999,
pages 821 ff.
The term "halogen" in each case denotes fluorine, chlorine, bromine or iodine,
preferably fluorine or chlorine;
"C1-C6-alkyr, as used herein, denotes a saturated straight-chain or branched
hydrocarbon group comprising from 1 to 6 carbon atoms, especially from 1 to 4 carbon
atoms, for example methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-
methylpropyl, 1,1-dimethylethyl, pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,
2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-
methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-
dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl,
1-ethyibutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-
methylpropyl, 1-ethyl-2-methylpropyl and isomers thereof. d-C4-Alkyl comprises, for
example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropy! or
1,1-dimethylethyl.
"C1-C4-haloalkyl" represents a partly or fully halogenated C1-C4-alkyl radical, where the
halogen atom(s) is/are especially fluorine, chlorine and/or bromine, i.e., for example,
chloromethyl, bromomethyl, dichloromethyl, trichloromethyl, fiuoromethyl, difluoro-
methyl, trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl,
1-chloroethyl, 1-bromoethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2-chloro-2-
fluoroethyl, 2,2,2-trifluoroethyl, 2-chloro-1,1,2-trifluoroethyl, 2-chloro-2,2-difluoroethyl,
2-bromo-2,2-difluoroethyl, 2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, 1,1,2,2-
tetrafluoroethyl, 1,1,2,2-tetrachloroethyl, pentafluoroethyl, 2,2,3,3-tetrafluoro-1 -propyl,
1,1,2,3,3,3-hexafluoro-1 -propyl, 1,1,1,3,3,3-hexafluoro-2-propyl, heptafluoro-1 -propyl,
heptafluoro-2-propyl, 2,2,3,3,4,4,4-heptafluoro-1-butyl or nonafluoro-1-butyl, especially
halomethyl, more preferably CH(F)2 and CF3;
"CrC4-alkoxy" represents methoxy, ethoxy, n-propoxy, 1-methylethoxy, n-butoxy, 1-
methyipropoxy, 2-methylpropoxy or 1,1-dimethylethoxy, especially 1-methylethoxy;
"C1-C4-haloalkoxy" represents a partly or fully halogenated C1-C4-alkoxy radical, where
the halogen atom(s) is/are especially fluorine, chlorine and/or bromine, i.e., for
example, OCH2CI, OCH2Br, OCHCb, OC(CI)3, OCH2F, OCHF2, OCF3, OCHFCI,
OCFCb, OCF2CI, OCHC1-CH3, OCHBr-CHs, OCHF-CH3, OCH2-CH2F, OCH2-CHF2,
OCH2-CHFCI, OCH2-CF3, OCF2-CHFCI, OCH2-CF2CI, OCH2-CF2Br, OCH2-CFCI2,
OCH2-C(CI)3, OCF2-CHF2, OC(CI)2-CHCI2, OC2F5, OCH2-CF2-CHF2, OCF2-CHF-CF3,
OCH(CF3)2, 0(n-C3F7), OCF(CF3)2,2,2,3,3,4,4,4-heptafluoro-1-butoxy or nonafluoro-1-
butoxy, especially OCF2-CHF-CF3.
The preparation of the following arylcarboxamides (I) is preferred:
benodanil, bixafen, boscalid, flutolanil, mepronil, penthiopyrad,
N-(2-bicyclopropyl-2-ylphenyl)-3-difluoromethyl-1-methylpyrazol-4-ylcarboxamide,
N-(3',4',5'-trifluorobiphenyl-2-yl)-1,3-dimethylpyrazol-4-ylcarboxamide,
N-(3',4',5'-trifluorobiphenyl-2-yl)-1,3-dimethyl-5-fluoropyrazol-4-ylcarboxamide,
N-(3',4',5'-trifluorobiphenyl-2-yl)-5-chloro-1,3-dimethylpyrazol-4-ylcarboxamide,
N-CS'^'.S'-trifluorobiphenyl^-yO-S-fluoromethyl-l-methylpyrazol^-ylcarboxamide,
N-(3',4',5'-trifluorobiphenyl-2-yl)-3-(chlorofluoromethyl)-1-methylpyrazol-4-
ylcarboxamide,
N-(3',4',5'-trifluorobiphenyl-2-yl)-3-difluoromethyl-1-methylpyrazol-4-ylcarboxamide,
N-(3',4',5'-trifluorobiphenyl-2-yl)-3-difluoromethyl-5-fluoro-1-methylpyrazol-4-
ylcarboxamide,
N-(3',4',5'-trifIuorobiphenyl-2-yl)-5-chloro-3-difluoromethyl-1-methylpyrazol-4-
ylcarboxamide,
N-(3,,4',5'-trifluorobiphenyl-2-yl)-3-(chlorodifIuoromethyl)-1-methylpyrazol-4-
ylcarboxamide,
N-(3',4',5'-trifluorobiphenyl-2-yl)-1-methyl-3-trifluoromethylpyrazol-4-ylcarboxamide,
N-(3,,4',5'-trifIuorobiphenyl-2-yl)-5-fluoro-1-methyl-3-trifIuoromethylpyrazol-4-
ylcarboxamide,
N-(3',4',5'-trifluorobiphenyl-2-yl)-5-chloro-1-methyl-3-trifluoromethylpyrazol-4-
ylcarboxamide,
N-(2',4',5'-trifIuorobiphenyl-2-yl)-1,3-dimethylpyrazol-4-ylcarboxamide,
N-(2',4',5'-trifluorobiphenyl-2-yl)-1,3-dimethyl-5-fluoropyrazol-4-ylcarboxamide,
N-(2',4',5'-trifluorobipheny!-2-yl)-5-chloro-1,3-dimethylpyrazol-4-ylcarboxamide,
N-(2'I4',5'-trifluorobiphenyl-2-yl)-3-fluoromethyl-1-methyIpyrazol-4-ylcarboxamide,
N-(2',4',5'-trifluorobiphenyl-2-yl)-3-(chlorofluoromethyl)-1-methylpyrazol-4-
ylcarboxamide,
N-(2',4',5'-trifluorobiphenyl-2-yl)-3-difluoromethyl-1-methylpyrazol-4-ylcarboxamide,
N-(2')4',5'-trifluorobiphenyl-2-yl)-3-difluoromethyl-5-fluoro-1-methylpyrazol-4-
ylcarboxamide,
N-(2',4',5'-trifluorobiphenyl-2-yl)-5-chloro-3-difluoromethyl-l-methylpyrazol-4-
yicarboxamide,
N-(2',4',5'-trifluorobiphenyl-2-yl)-3-(chlorodifluoromethyl)-1-methylpyrazol-4-
ylcarboxamide,
N-(2',4',5'-trifluorobiphenyl-2-yl)-1-methyl-3-trifluoromethylpyrazol-4-ylcarboxamide,
N-(2',4',5'-trifluorobiphenyl-2-yl)-5-fIuoro-1-methyl-3-trifluoromethylpyrazol-4-
ylcarboxamide,
N-(2',4',5'-trifluorobiphenyl-2-yl)-5-chloro-1-methyl-3-trifIuoromethylpyrazol-4-
ylcarboxamide,
N-(3',4,-dichloro-3-fluorobiphenyl-2-yl)-1-methyl-3-trifIuoromethyl-1H-pyrazol-4-
ylcarboxamide,
N-(3',4'-dichloro-3-fluorobiphenyl-2-yl)-1-methyl-3-difluoromethyl-IH-pyrazol-4-
ylcarboxamide,
N-(3',4'-difluoro-3-fluorobiphenyl-2-yl)-1-methyl-3-trifluoromethyl-IH-pyrazol-4-
carboxamide,
N-(3',4'-difluoro-3-fluorobiphenyl-2-yl)-1-methyl-3-difluoromethyl-IH-pyrazol-4-
ylcarboxamide,
N-(3'-chloro-4'-fluoro-3-fluorobiphenyl-2-yl)-1-methyl-3-difluoromethyl-IH-pyrazol-4-
ylcarboxamide,
N-(3',4'-dichloro-4-fluorobiphenyl-2-yl)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-
ylcarboxamide,
N-(3',4'-difluoro-4-fluorobiphenyl-2-yl)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-
ylcarboxamide,
N-(3',4'-dichloro-4-fluorobiphenyl-2-y!)-1-methyl-3-difIuoromethyl-1H-pyrazol-4-
ylcarboxamide,
N-(3',4'--difluoro-4-fluorobiphenyl-2-yl)-1-methyl-3-difluoromethyl-IH-pyrazol-4-
ylcarboxamide,
N-(3'-chloro-4,-fluoro-4-fluorobiphenyl-2-yl)-1-methyl-3-difluoromethyl-1H-pyrazol-4-
ylcarboxamide,
N-(3',4'-dichloro-5-fluorobiphenyl-2-yl)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-
ylcarboxamide,
N-(3',4'-difluoro-5-fluorobiphenyl-2-yl)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-
ylcarboxamide,
N-(3',4'-dichloro-5-fluorobiphenyl-2-yl)-1-methyl-3-difluoromethyl-1H-pyrazol-4-
ylcarboxamide,
N-(3,,4'-difluoro-5-fIuorobiphenyl-2-yl)-1-methyl-3-difIuoromethyl-1H-pyrazol-4-
ylcarboxamide,
N-(3',4'-dichloro-5-fluorobiphenyl-2-yl)-1,3-dimethyl-1H-pyrazol-4-ylcarboxamide,
N-(3'-chloro-4'-fluoro-5-fluorobiphenyl-2-yl)-1-methyl-3-difluoromethyl-1H-pyrazol-4-
ylcarboxamide,
N-(4'-fluoro-4-fluorobiphenyl-2-yl)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-
ylcarboxamide,
N-(4'-fluoro-5-fluorobiphenyl-2-yl)-1-methyl-3-trifIuoromethyl-1H-pyrazol-4-
ylcarboxamide,
N-(4'-chloro-5-fluorobiphenyl-2-yl)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-
ylcarboxamide,
N-(4'-methyl-5-fluorobiphenyl-2-yl)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-
ylcarboxamide,
N-(4'-fluoro-5-fIuorobiphenyl-2-yl)-1,3-dimethyl-1H-pyrazol-4-ylcarboxamide,
N-(4'-chloro-5-fluorobiphenyl-2-yl)-1,3-dimethyl-1H-pyrazol-4-ylcarboxamide,
N-(4'-methyl-5-fluorobiphenyl-2-yl)-1,3-dimethyl-1H-pyrazol-4-ylcarboxamide,
N-(4'-fIuoro-6-fluorobiphenyl-2-yl)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-
ylcarboxamide,
N-[2-(1,1,2,3,3,3-hexafIuoropropoxy)phenyl]-3-difluoromethyl-1-methyl-
1 H-pyrazol-4-ylcarboxamide,
N.[4'.(trifluoromethylthio)biphenyl-2-yl]-3-difluoromethyl-1-methyl-1H-pyrazol-
4-ylcarboxamide,
N-[4'-(trifluoromethylthio)biphenyl-2-yl]-1-methyi-3-trifluoromethyl-1-methyl-1H-pyrazol-
4-ylcarboxamide,
3-(difluoromethyl)-1-methyl-N-[1,2,3,4-tetrahydro-9-(1-methylethyl)-1,4-
methanonaphthalen-5-yl]-1H-pyrazol-4-ylcarboxamide,
N-(3'-chloro-5-fluorobiphenyl-2-yl)-3-(difluoromethyl)-1-methylpyrazol-4-ylcarboxamide,
N-(4'-chloro-5-fluorobiphenyl-2-yl)-3-(difluoromethyl)-1-methylpyrazol-4-ylcarboxamide,
N-(4'-chlorobiphenyl-2-yl)-3-(ciifluoromethyl)-1-methylpyrazol-4-ylcarboxamicle,
N-(4'-bromobiphenyl-2-yl)-3-(difluoromethyl)-1-methylpyrazol-4-ylcarboxamide,
N-(4'-iodobiphenyl-2-yl)-3-(difluoromethyl)-1-methylpyrazol-4-ylcarboxamide,
N-(3',5'-difluorobiphenyl-2--yl)-3-(difluoromethyl)-1-methylpyrazol-4-ylcarboxamide,
N-(2-chloro-4-fluoropheny!)-3-(difluoromethyl)-1-methylpyrazol-4-ylcarboxamide,
N-(2-bromo-4-fluorophenyl)-3-(difluoromethyl)-1-methylpyrazol-4-ylcarboxamide,
N-(2-iodo-4-fluorophenyl)-3-(difIuoromethyl)-1-methylpyrazol-4-ylcarboxamide or
N-[2-(1,3-dimethylbutyl)phenyl]-1,3-dimethyl-5-fIuoro-1 H-pyrazol-4-ylcarboxamide.
Particular preference is given to those carboxamides (I) in which
Ar is a mono- to trisubstituted pyridyl or pyrazolyl ring, where the substituents are each
independently selected from halogen, C1-C4-alkyl and C1-C4-haloalkyl. Very particular
preference is given to those carboxamides (I) in which Ar is a di- or trisubstituted
pyrazolyl ring, where the substituents are each independently selected from halogen,
C1-C4-alkyl and C1-C4-haloalkyl, especially fluorine, chlorine, methyl, difluoromethyl and
trifluoromethyl.'
According to the invention, the reaction is conducted without an auxiliary base in an
organic solvent which is substantially anhydrous. A low water content is understood to
mean from about 0.5 g to 5 g of water per mole of acid chloride (II) used. Larger
amounts of water should be avoided, since the water would lead to an increased
consumption of feedstocks.
Usable solvents are, for example, aromatic hydrocarbons such as toluene, o-, m-, p-
xylene, mesitylene, ethylbenzene and chlorobenzene, halogenated aliphatic
hydrocarbons such as tetrachloroethane and dichloroethylene, ethers such as methyl
tert-butyl ethyl, tetrahydrofuran and dioxane or mixtures of the solvents mentioned.
Particularly preferred solvents are the aromatic hydrocarbons, especially toluene and
o-, m-, p-xylene.
According to the invention, the acid chloride (II) is initially charged, the desired
pressure is established and the arylamine (III) is metered in. Metered addition is
understood to mean both the addition of (III) in portions and the continuous addition of
(III)
a) to the surface of the solution of (II) or
b) directly into the solution of (II), as an "immersed mode of reaction".
The pressure is generally selected such that the reaction mixture boils.
It is normal to work at a pressure between 0 and 700 mbar and a reaction temperature
of from 20 to 120°C, preferably at from 200 to 600 mbar and from 70 to 100°C,
especially at from 350 to 450 mbar and 80 to 90°C.
Acid chloride (II) and arylamine (III) are used in about equimolar amounts, or one of the
components is used in a slight excess of up to 10 mol%. The molar ratio of (III) to (II) is
thus generally from 0.9 :1 to 1.1 :1, preferably from about 1.0 to 1.1.
The metered addition of (III), preferably dissolved in the organic solvent in which (II)
has also been initially charged, is effected typically over the course of from 0.5 to 20
hours, especially from 2 to 10 hours, more preferably from 3 to 5 hours.
The carboxamide (I) is released from the reaction mixture preferably by direct
crystallization or by treatment of the reaction mixture with a suitable base and
subsequent crystallization, for example at from (-20) to 20°C.
Suitable bases for this purpose are alkali metal hydroxides such as sodium and
potassium hydroxide, alkali metaj carbonates such as sodium and potassium
carbonate, alkali metal hydrogencarbonates such as sodium and potassium
hydrogencarbonate, alkali metal phosphates such as sodium and potassium
phosphate, alkali metal hydrogenphosphates such as sodium and potassium hydrogen-
phosphate, alkali metal dihydrogenphosphates such as sodium and potassium
dihydrogenphosphate, and also nitrogen bases such as ammonia.
Particular preference is given to the alkali metal hydroxides such as sodium and
potassium hydroxide, alkali metal carbonates such as sodium and potassium
carbonate, and also to the alkali metal hydrogencarbonates such as sodium and
potassium hydrogencarbonate.
The base can be used in solid form or in the form of its commercial aqueous solutions.
Preference is given to using a from 1 to 20% by weight aqueous solution, the amount
preferably being such that the pH of the solution is from 3 to 12, preferably from 7 to
10.
The crystalline product of value can finally be removed by means of customary
methods, for example filtration.
The process products (I) are valuable active ingredients in crop protection.
Working examples:
Example 1
Synthesis of N-(3',4',5'-trifluorobiphenyl-2-yl)-3-difluoromethyl-1-methyl-1 H-pyrazole-4-
carboxamide
100.0 g (0.504 mol, 98% pure) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl
chloride were dissolved at 25°C in 257.2 g of toluene. The solution was evacuated to
400 mbar and heated to 85°C. Subsequently, within 3 hours, 492.8 g (0.499 mol, 23%
strength) of toluenic 3',4',5'-trifluorobiphenyl-2-ylamine solution were metered in, after
which stirring was continued for another 1 hour. After venting and cooling to 25°C with
a ramp of 10°C/h, the mixture was stirred overnight. Subsequently, the mixture was
cooled to 0°C, and the solid constituents were filtered off, washed with cold toluene and
dried at 80°C under reduced pressure. The yield (without further processing of the
mother liquor) was 177.7 g (92%).
Example 1a (comparative test)
Synthesis of N-(3',4',5'-trifluorobiphenyl-2-yl)-3-difluoromethyl-1-methyl-1 H-pyrazole-4-
carboxamide (analogous mode of reaction to example 1 from JP-A 2001/172276, p. 10)
19.0 g (0.085 mol, 99.8% pure) of 3',4',5'-trifluorobiphenyl-2-ylamine were dissolved in
400.0 g of toluene. Within 1 min, 17.7 g (0.089 mol, 98.1% pure) of 3-difluoromethyl-1-
methyl-1 H-pyrazole-4-carbonyl chloride were added at 25°C. Subsequently, the
reaction mixture was evacuated to 72 mbar and heated to 40°C for 3 hours. After
15 min, a white solid formed, which was later converted to a viscous, gel-like
suspension. After cooling to 0°C, the mixture was filtered through a glass frit (very slow,
blockages) and the filtercake was washed with cold toluene. The residue was dried
under reduced pressure and afforded 15.0 g of a mixture of 3',4',5'-trifluorobiphenyl-2-
ylamine hydrochloride (40% by weight) and N-(3',4',5'-trifluorobiphenyl-2-yl)-3-
difluoromethyl-1-methyl-1H-pyrazole-4-carboxamide (48% by weight). The mother
liquor (375.0 g) comprised 2.8% by weight of N-(3',4',5'-trifluorobiphenyl-2-yl)-3-
difluoromethyl-1-methyl-1H-pyrazole-4-carboxamide. Purely theoretically, the yield was
thus approx. 54%.
Example 2
Synthesis of N-(3',5'-difluorobiphenyl-2-yl)-3-difluoromethyl-1-methyl-1 H-pyrazole-4-
carboxamide
38.9 g (0.196 mol, 98% pure) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl
chloride were dissolved at 25°C in 100.0 g of toluene. The solution was evacuated to
400 mbar and heated to 85°C. Subsequently, within 1.5 hours, 173.0 g (0.194 mol,
23% strength) of toluenic 3',4*-difluorobiphenyl-2-ylamine solution were metered in and
the reaction mixture was stirred for a further 1 hour. After venting and cooling to room
temperature, the mixture was concentrated to volume approx. 100 ml under reduced
pressure. The solids were filtered off, washed with n-hexane and dried at 85°C under
reduced pressure. The yield (without further processing of the mother liquor) was
46.5 g (66%).
Example 3
Synthesis of N-(3',4',5'-trifluorobiphenyl-2-yl)-1,3-dimethyl-1 H-pyrazole-4-carboxamide
79.1 g (0.494 mol, 99% pure) of 1,3-dimethyl-1H-pyrazole-4-carbonyl chloride were
dissolved at 25°C in 257.2 g of toluene. The solution was evacuated to 400 mbar and
heated to 85°C. Subsequently, within 3 hours, 483.0 g (0.489 mol, 23% strength) of
toluenic 3',4',5'-trifluorobiphenyl-2-ylamine solution were metered in and the reaction
mixture was stirred for a further 1 hour. After venting and cooling to 70°C, the mixture
was cooled to 20°C with a cooling ramp of 5°C/h and stirred overnight. Subsequently,
the mixture was cooled to 0°C, and the solids were filtered off, washed with cold
toluene and dried at 80°C under reduced pressure. The yield (without further
processing of the mother liquor) was 155.4 g (92%).
Example 4
Synthesis of N-(2-chlorophenyl)-3-difluoromethyl-1-methyl-1 H-pyrazole-4-carboxamide
80.0 g (0.403 mol, 98% pure) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl
chloride were dissolved at 25°C in 257.2 g of toluene. The solution was evacuated to
400 mbar and heated to 85°C. Subsequently, within 3 hours, 221.3 g (0.399 mol, 23%
strength) of toluenic 2-chloroaniline solution were metered in and the reaction mixture
was stirred for a further 1 hour. After venting and cooling to 20°C with a ramp of
10°C/h, the mixture was stirred overnight. Subsequently, the mixture was cooled to
0°C, and the solids were filtered off, washed with cold toluene and dried at 80°C under
reduced pressure. The yield (without further processing of the mother liquor) was 105 g
(92%).
Example 5
Synthesis of N-(3',4'-dichloro-5-fluorobiphenyl-2-yl)-3-difluoromethyl-1-methyl-1 H-
pyrazole-4-carboxamide
5.6 g (0.029 mol, 98% pure) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl
chloride were dissolved at 25°C in 10.4 g of toluene. The solution was evacuated to
400 mbar and heated to 85°C. Subsequently, within 5 minutes, 7.8 g (0.030 mol,
approx. 92% pure) of 3',4'-dichloro-5-fluorobiphenyl-2-ylamine, dissolved in 28 g of
toluene, were metered in and the reaction mixture was stirred for a further 1 hour. After
venting and cooling to 25°C overnight, the mixture was cooled further to 0°C, and the
solids were filtered off, washed with cold toluene and dried at 80°C under reduced
pressure. The yield (without further processing of the mother liquor) was 8.1 g (71%).
Example 6
Synthesis of N-(2-bicyclopropyl-2-yiphenyl)-3-difluoromethyl-1 -methyl-1 H-pyrazole-4-
carboxamide
16.7 g (0.086 mol, 98% pure) of 3-difiuoromethyl-1-methyl-1H-pyrazole-4-carbony[
chloride were dissolved at 25°C in 48.0 g of toluene. The solution was evacuated to
400 mbar and heated to 85°C. Subsequently, within 45 min, 15.0 g (0.087 mol) of 2-
bicyclopropyl-2-ylphenylamine, dissolved in 51.6 g of toluene, were metered in and the
reaction mixture was stirred for another 1 h. After venting and cooling to 25°C, the
mixture was stirred overnight. Subsequently, the mixture was concentrated under
reduced pressure and dried. The yield was 27.3 g (96%).
Example 7
Synthesis of N-(9-isopropyl-1,2,3,4-tetrahydro-1,4-methanonaphthalen-5-yl)-3-
difluoromethyl-1 -methyl-1 H-pyrazole-4-carboxamide
15.1 g (0.0752 mol, 96.5% pure) of 3-difluoromethyl-1 -methyl-1 H-pyrazole-4-carbonyl
chloride were dissolved at 25°C in 100 ml of toluene. The solution was evacuated to
350 mbar and heated to 85°C. Subsequently, within 60 min, 20 g (0.074 mol, 75%;
65:10 syn/anti isomer mixture) of 9-isopropyl-1,2,3,4-tetrahydro-1,4-methano-
naphthalen-5-ylamine, dissolved in 100 ml of toluene, were metered in and the reaction
mixture was stirred for another 1 hour. After venting and cooling to 25°C, the mixture
was stirred overnight. Subsequently, the mixture was concentrated under reduced
pressure and dried. The yield was 31.3 g; according to 1H NMR 70% pure (82%).
Example 8
Synthesis of 2-chloro-N-(4'-chlorobiphenyl-2-yl)nicotinamide
100.0 g (0.557 mol, 98% pure) of 3-difluoromethyl-1 -methyl-1 H-pyrazole-4-carbonyl
chloride were dissolved at 25°C in 80.0 g of toluene. The solution was evacuated to
200 mbar and heated to 95°C. Subsequently, within 2.5 hours, 396.8 g (0.541 mol,
28% strength) of xylenic 4'-chlorobiphenyl-2-ylamine solution were metered in and the
reaction mixture was stirred for a further 1 hour. After venting and cooling to 87°C, the
mixture was seeded with 1 g of 2-chloro-N-(4'-chlorobiphenyl-2-yl)nicotinamide and the
temperature was maintained for 1 hour. Subsequently, the mixture was cooled to 25°C
with a ramp of 5°C/h. After further cooling to 10-15°C, the solids were filtered off,
washed with cold xylene and dried at 80°C under reduced pressure. The yield (without
further processing of the mother liquor) was 166.4 g (73%). HPLC shows the desired
product and the diacylated product in a ratio of 85:15 area%.
Claims
1. A process for preparing aryicarboxamides of the formula (I)

where the substituents are each defined as follows:
Ar is a mono- to trisubstituted phenyl, pyridyl or pyrazolyl ring, where the
substituents are each independently selected from halogen, C1-C4-alkyl and
C1-C4-haloalkyl;
M is thienyl or phenyl, which may bear a halogen substituent;
Q is a direct bond, cyclopropylene, a fused bicyclo[2.2.1]heptane or
bicyclo[2.2.1]heptene ring;
R1 is hydrogen, halogen, C1-C6-alkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, mono- to
trisubstituted phenyl, where the substituents are each independently selected
from halogen and trifiuoromethylthio, or cyclopropyl;
by reacting an acid chloride of the formula (II)

with an arylamine (111)

in a suitable nonaqueous solvent,
which comprises, in the absence of an auxiliary base,
a) initially charging the acid chloride (II),
b) establishing a pressure of from 0 to 700 mbar,
c) metering in the arylamine (III) in an approximately stoichiometric amount
and
d) isolating the product of value.
2. The process according to claim 1, wherein Ar is a phenyl, pyridyi or pyrazolyl ring

and
R2 is halogen, methyl or trifluoromethyl;
R3 is halogen;
R4 is C1-C4-all R5 is hydrogen or halogen.
3. The process according to claim 1, wherein M is phenyl, Q is cyclopropylene and
R1 is cyclopropyl.
4. The process according to claim 1, wherein M is phenyl, Q is a bond and R1 is
isopropoxy or mono- to trisubstituted phenyl, where the substituents are each
independently selected from halogen and trifluoromethylthio.
5. The process according to claim 1, wherein M is phenyl substituted by one
halogen, Q is a bond and R1 is hydrogen or mono- to tri-halogen-substituted
phenyl.
6. The process according to claim 1, wherein the arylcarboxamide is benodanil,
bixafen, boscalid, flutolanil, mepronil, penthiopyrad,
N-(2-bicyclopropyl-2-ylphenyl)-3-difluoromethyl-1-methylpyrazol-4-ylcarboxamide,
N-(3',4',5'-trifluorobiphenyl-2-yl)-1,3-dimethylpyrazol-4-ylcarboxamide,
N-(3',4',5'-trifluorobiphenyl-2-yl)-1,3-dimethyl-5-fluoropyrazol-4-ylcarboxamide,
N-(3',4',5'-trifluorobiphenyl-2-yl)-5-chloro-1,3-dimethylpyrazol-4-ylcarboxamide,
N-(3',4',5'-trifiuorobiphenyl-2-yl)-3-fluoromethyl-1-methylpyrazol-4-ylcarboxamide,
N-(3',4',5'-trifluorobiphenyl-2-yl)-3-(chlorofluoromethyl)-1-methylpyrazol-4-
ylcarboxamide,
N-(3',4',5'-trifluorobiphenyl-2-yl)-3-difluoromethyl-1-methylpyrazol-4-
ylcarboxamide,
N-(3',4',5'-trifiuorobiphenyl-2-yl)-3-difluoromethyl-5-fluoro-1-methylpyrazol-4-
ylcarboxamide,
N-(3',4'I5'-trifluorobiphenyl-2-yl)-5-chloro-3-difIuoromethyl-1-methylpyrazol-4-
ylcarboxamide,
N-(3',4'I5'-trifluorobiphenyl-2-yl)-5-chloro-3-difIuoromethyl-1-methylpyrazol-4-
ylcarboxamide,
N-(3',4'I5'-trifluorobiphenyl-2-yl)-5-chloro-3-difIuoromethylpyrazol-4-
ylcarboxamide,
N-(3',4',5'-trifluorobiphenyl-2-yl)-5-fIuoro-1-methyl-3-trifluoromethylpyrazol-4-
ylcarboxamide,
N-(3',4',5'-trifluorobiphenyl-2-yl)-5-chloro-1-methyl-3-trifluoromethylpyrazol-4-
ylcarboxamide,
N-(2',4',5'-trifIuorobiphenyl-2-yl)-1,3-dimethylpyrazol-4-ylcarboxamidel
N-(2',4',5'-trifluorobiphenyl-2-yl)-1,3-dimethyl-5-fluoropyrazol-4-ylcarboxamide,
N-(2',4',5'-trifluorobiphenyl-2-yl)-5-chloro-1,3-dimethylpyrazo!-4-ylcarboxamidel
N-(2',4',5'-trifluorobiphenyl-2-yl)-3-fluoromethyl-1-methylpyrazol-4-ylcarboxamide,
N-(2',4',5'-trifluorobiphenyl-2-yl)-3-(chlorofluoromethyl)-1-methyipyrazol-4-
ylcarboxamide,
N-(2',4',5'-trifluorobiphenyl-2-yl)-3-difluoromethyl-1-methylpyrazol-4-
ylcarboxamide,
N-(2',4',5'-trifluorobiphenyl-2-yl)-3-difIuoromethyl-5-fluoro-1-methylpyrazol-4-
ylcarboxamide,
N-(2',4',5'-trifluorobiphenyl-2-yl)-5-chloro3-difIuoromethyl-1-methylpyrazol-4-
ylcarboxamide,
N-(2',4',5'-trifluorobiphenyl-2-yl)-3-(chlorodifluoromethyl)-1-methylpyrazol-4-
ylcarboxamide,
N-(2',4',5'-trifluorobiphenyl-2-yl)-1-methyl-3-trifluoromethylpyrazol-4-
ylcarboxamide,
N-(2',4',5'-trifluorobiphenyl-2-yl)-5-fluoro-1-methyl-3-trifluoromethylpyrazol-4-
ylcarboxamide,
N-(2'I4',5'-trifluorobiphenyl-2-yl)-5-chloro-1-methyl-3-trifluoromethylpyrazol-4-
ylcarboxamide,
N-(3',4'-dichloro-3-fluorobiphenyl-2-yl)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-
ylcarboxamide,
N-(3',4'-dichloro-3-fluorobiphenyl-2-yl)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-
ylcarboxamide,
N-(3',4'-dichloro-3-fluorobiphenyl-2-yl)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-
carboxamide,
N-(3',4'-dichloro-3-fluorobiphenyl-2-yl)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-
ylcarboxamide,
N-(3',4'-dichloro-3-fluorobiphenyl-2-yl)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-
4-ylcarboxamide,
N-(3',4'-dichloro-3-fluorobiphenyl-2-yl)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-
ylcarboxamide,
N-(3',4'-clifluoro-4-fIuorobiphenyl-2-yl)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-
ylcarboxamide,
N-(3,,4,-dichloro-4-fIuorobiphenyl-2-yl)-1-methyl-3-difluoromethyl-1H-pyrazol-4-
ylcarboxamide,
N-(3',4'-difluoro-4-fluorobiphenyl-2-yl)-1-methyl-3-difluoromethyl-1H-pyrazol-4-
ylcarboxamide,
N-(3,-chloro-4'-fluoro-4-fluorobiphenyl-2-yl)-1-methyl-3-difluoromethyl-1H-pyrazol-
4-ylcarboxamide,
N-(3,,4,-dichloro-5-fluorobiphenyl-2-yl)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-
ylcarboxamide,
N-(3',4'-difluoro-5-fluorobiphenyl-2-yl)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-
ylcarboxamide,
N-(3',4,-dichloro-5-fluorobiphenyl-2-yl)-1-methyl-3-difluoromethyl-1H-pyrazol-4-
ylcarboxamide,
N-(3',4'-difluoro-5-fluorobiphenyl-2-yl)-1-methyl-3-difluoromethyl-1H-pyrazol-4-
ylcarboxamide,
N-(3',4'-dichloro-5-fluorobiphenyl-2-yl)-1,3-dimethyl-1H-pyrazol-4-ylcarboxamide,
N-(3'-chloro-4'-fluoro-5-fluorobiphenyl-2-yl)-1-methyl-3-difluoromethyl-1H-pyrazol-
4-ylcarboxamide,
N-(4'-fluoro-4-fluorobiphenyl-2-yl)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-
ylcarboxamide,
N-(4'-fluoro-5-fluorobiphenyl-2-yl)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-
ylcarboxamide,
N-(4'-chloro-5-fluorobiphenyl-2-yl)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-
yicarboxamide,
N-(4,-methyl-5-fluorobiphenyl-2-yl)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-
ylcarboxamide,
N-(4'-fluoro-5-fluorobiphenyl-2-yl)-1,3-dimethyl-1H-pyrazol-4-ylcarboxamide,
N-(4,-chloro-5-fluorobiphenyl-2-yl)-1,3-dimethyl-1H-pyrazol-4-ylcarboxamide,
N-(4'-methyl-5-fluorobiphenyl-2-yl)-1,3-dimethyl-1H-pyrazol-4-ylcarboxamide,
N-(4'-fluoro-6-fluorobiphenyl-2-yl)-1-methyl-3-trifluoromethyl-1H-pyrazol-4-
ylcarboxamide,
N-[2-(1,1 ,2,3,3,3-hexafluoropropoxy)phenyl]-3-difluoromethyl-l-methyl-
1 H-pyrazol-4-ylcarboxamide,
N-[4'-(trifluoromethylthio)biphenyl-2-yl]-3-difluoromethyl-1-methyl-1H-pyrazol-
4-ylcarboxamide,
N-[4'-(trifIuoromethylthio)biphenyl-2-yl]-1-methyl-3-trifluoromethyl-1-methyl-1H-
pyrazol-4-ylcarboxamide,
3-(difluoromethyl)-1-methyl-N-[1,2,3,4-tetrahydro-9-(1-methylethyl)-1,4-
methanonaphthalen-5-yl]-1H-pyrazol-4-ylcarboxamide,
N-(3'-chloro-5-fluorobiphenyl-2-yl)-3-(difiuoromethyl)-1-methylpyrazol-4-
ylcarboxamide,
N-(4'-chloro-5-fIuorobiphenyl-2-yl)-3-(difluoromethyl)-1-methylpyrazol-4-
ylcarboxamide,
N-(4'-chlorobiphenyl-2-yl)-3-(difluoromethyl)-1-methylpyrazol-4-ylcarboxamide,
N-(4'-bromobiphenyl-2-yl)-3-(drfluoromethyl)-1-methylpyrazol-4-ylcarboxamide,
N-(4'-iodobiphenyl-2-yl)-3-(difluoromethyl)-1-methylpyrazol-4-ylcarboxamide,
N-(3',5'-difluorobiphenyl-2-yl)-3-(difluoromethyl)-1-methylpyrazol-4-
ylcarboxamide,
N-(2-chloro-4-fluorophenyl)-3-(difluoromethyl)-1-methylpyrazol-4-ylcarboxamide,
N-(2-bromo-4-fluorophenyl)-3-(difluoromethyl)-1-methylpyrazol-4-ylcarboxamide,
N-(2-iodo-4-fluoropheny!)-3-(difluoromethyl)-1-methylpyrazol-4-ylcarboxamide or
N-[2-(1,3-dimethylbutyl)phenyl]-1,3-dimethyl-5-fluoro-1 H-pyrazol-4-
ylcarboxamide.
7. The process according to claim 1, wherein the reaction of II with III is undertaken
at a pressure of from 200 to 600 mbar.
8. The process according to claim 1, wherein the reaction of II with III is undertaken
at from 20 to120°C.
9. The process according to claim 1, wherein the molar ratio of II to III is from 0.9 : 1
to 1.1 : 1.
10. The process according to claim 1, wherein the starting material is an arylamine III
which has been obtained by hydrogenating the corresponding nitroaryl.


Method for manufacturing aryl carboxamides
of the formula (I), with Ar = singly to triply substituted
phenyl, pyridyl or pyrazolyl rings, wherein the substituents
are selected from halogen, C1-C4 alkyl and C1-C4 halogen
alkyl; M = thienyl or phenyl, which can contain a halogen
substituent; Q = direct bond, cyclopropylene, annulated bicyclo
[2.2.1 ]heptane or bicyclo[2.2.1 ]heptene ring; R1 =
hydrogen, halogen, C1-C6 alkyl, C1-C4 alkoxy, C1-C4 halogen
alkoxy, singly to triply substituted phenyl, wherein the
substituents are selected from halogen and trifluoromethylthio,
or cyclopropyl; through reaction of an acid chloride of
the formula (II) with an aryl amine (III) in a suitable nonaqueous
solvent, wherein in the absence of an auxiliary
base a) the acid chloride (II) is added, b) a pressure of 0 to
700 mbar is established, c) the aryl amine (III) is added in
approximately stoichiometric amounts and d) the valuable
product is isolated.

Documents:

http://ipindiaonline.gov.in/patentsearch/GrantedSearch/viewdoc.aspx?id=p28XkMwcehRHcclFKP/rwQ==&loc=wDBSZCsAt7zoiVrqcFJsRw==


Patent Number 280054
Indian Patent Application Number 3903/KOLNP/2010
PG Journal Number 06/2017
Publication Date 10-Feb-2017
Grant Date 08-Feb-2017
Date of Filing 19-Oct-2010
Name of Patentee BASF SE
Applicant Address 67056 LUDWIGSHAFEN GERMANY
Inventors:
# Inventor's Name Inventor's Address
1 REICHERT, WOLFGANG HANNS-FAYSTR. 3,67227 FRANKENTHAL GERMANY
2 RACK, MICHAEL HILDASTR. 11/1, 69214 EPPELHEIM GERMANY
3 ZIERKE, THOMAS AKAZIENSTR. 12, 67459 BÖHL-IGGELHEIM GERMANY
4 KEIL, MICHAEL FONTANESTR. 4, 67251 FREINSHEIM GERMANY
5 KORADIN, CHRISTOPHER RIEDLANGSTR. 15, 67067 LUDWIGSHAFEN GERMANY
6 SMIDT, SEBASTIAN PEER ERNST-BARLACH-STR. 12, 68723 OFTERSHEIM GERMANY
7 MAYWALD, VOLKER CHRISTOPH-KRÖWERATH, STR. 72, 67071 LUDWIGSHAFEN GERMANY
8 WOLF, BERND HALBERGSTR. 4, 67136 FUSSGÖNHEIM GERMANY
PCT International Classification Number C07D 213/82
PCT International Application Number PCT/EP2009/055446
PCT International Filing date 2009-05-06
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 08155888.4 2008-05-08 EUROPEAN UNION