Process for the preparation of pyrazole-4-carboxamides
The invention concerns a process for the manufacture of lH-pyrazole-4-
carboxamides, in particular 3-difluoromethyl-l -methyl- lH-pyrazole-4-
carboxamides, which are useful as pharmaceuticals and agrochemicals.
Particular examples of 3-difluoromethyl-l -methyl- lH-pyrazole-4-
carboxamides are for instance Bixafen, Sedaxane, Isopyrazam and Fluxapyraxad.
Bixafen having the chemical name N-(3',4'-dichloro-5-fluoro-[l,l'-
biphenyl]-2-yl)-3-(difluoro- methyl)-l -methyl- lH-pyrazole-4-carboxamide
(CAS Number 581809-46-3) and its manufacturing process is described
in WO 03/070705.
Sedaxane is a mixture of isomers N-(2-[l,l'-bicyclopropyl]-2-ylphenyl)-3-
(difluoromethyl)- 1-methyl lH-pyrazole-4-carboxamide
(CAS Number 874967-67-6). Sedaxane and its manufacturing process are for
example described in WO 2006/015865 and WO 2006/015866.
Isopyrazam is a mixture of isomers of 3-(difluoromethyl)-l-methyl-N-
[l,2,3,4-tetrahydro-9-isopropyl-l,4-methanonaphthalen-5-yl]pyrazole-4-
carboxamide (CAS Number 881685-58-1). Isopyrazam and its manufacturing
process are described in WO 2004/035589.
Fluxapyroxad having the chemical name 3-(Difluoromethyl)-l-methyl-N-
(3',4',5'-trifluorobiphenyl- 2-yl)-lH-pyrazole-4-carboxamide and its
manufacturing process is described in WO 2006/087343.
lH-pyrazole-4-carboxamides are generally obtained by reacting the
corresponding 4-carboxylic acid pyrazole or the activated form of said
carboxylic acid, for example an acid chloride, with an appropriate amine, see for
example WO 03/070705 (EP1490342), WO 2005/123690, WO 2006/087343
or WO 2007/009717.
US5556987 describes a process for the production of
5-hydroxypyrazolecarboxamides which is catalysed with a Lewis acid such
as A1C13.
It is an object of the present invention to provide a process for the synthesis
of lH-pyrazole-4-carboxamides which allows, in particular, in an economically
manner for high yield, high purity, and high efficiency for the manufacture of the
target product. The process can have environmental benefits.
The invention consequently relates to a process for the manufacture of for
the manufacture of compounds of formula (I)
wherein
R2 is H or an organic residue
R3 is H, a halogen, an aliphatic, which also comprises alicyclic,
heteroaliphatic, which also comprises heterocyclic, heteroaromatic or
aromatic group, in particular an alkyl group having from 1 to 12 carbon
atoms, a halogenated alkyl group having from 1 to 12 carbon atoms, an
aralkyl group, an aryl group
R4 is H, a halogen, an aliphatic, which also comprises alicyclic,
heteroaliphatic, which also comprises heterocyclic, heteroaromatic or
aromatic group, in particular an alkyl group having from 1 to 12 carbon
atoms, a halogenated alkyl group having from 1 to 12 carbon atoms, an
aralkyl group, an aryl group,
X is oxygen or sulfur
Q is an alicyclic, heterocyclic, heteroaromatic or aromatic group, in particular
a group of any of formulae (Ql) to (Q38) herein below:

(Q36) (Q37) (Q38)
wherein R6 is a hydrogen, C1-12 alkyl, C2-12 alkenyl or C2-12 alkynyl group, which
may be substituted by 1 to 6 substituents, each substituent independently selected
from halogen, cyano, Ci_4 alkoxy, C1-4 thioalkyl, COO-Ci_ alkyl, =N-OH,
=N-0-(Ci_4 alkyl), C3_ cycloalkyl, which may itself be substituted by 1
to 3 substituents, each independently selected from C1-4 alkyl, halogen,
Ci-4 alkoxy and C1-4 haloalkoxy, and C4_ cycloalkenyl, which may itself be
substituted by 1 to 3 substituents, each independently selected from C1-4 alkyl,
halogen, C1-4 alkoxy and C1-4 haloalkoxy ;
or R6 is a C3 8 cycloalkyl, C4_8 cycloalkenyl or C 5- cycloalkadienyl group, which
may be substituted by 1 to 3 substituents, each independently selected from
halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 thioalkyl,
C3_6 cycloalkyl, which may itself be substituted by 1 to 3 substituents, each
independently selected from C1-4 alkyl, halogen, C1-4 alkoxy and C1-4 haloalkoxy,
and phenyl, which may itself be substituted by 1 to 5 independently selected
halogen atoms ;
or R6 is a C6-i2 bicycloalkyl, C6-i2 bicycloalkenyl or C6-i2 bicycloalkadienyl
group, which may be substituted by 1 to 3 substituents, each independently
selected from halogen, C1-4 alkyl and C1-4 haloalkyl ;
or R6 is phenyl, which may be substituted by 1 to 3 substituents, each
independently selected from halogen, cyano, nitro, C1-4 alkyl, C1-4 haloalkyl,
Ci_ alkoxy, C1-4 alkylthio, C1-4 haloalkoxy, C1-4 haloalkylthio, C(H)=N-OH,
C(H)=N-0(Ci_6 alkyl), C(C 1-6 alkyl)=N-OH, C(C 1-6 alkyl)=N-0-(Ci_ 6 alkyl),
(Z)CºCR, (Z) CR28 =CR26 R27 , phenyl, which may itself be substituted by 1
to 3 substituents, each independently selected from halogen, cyano, nitro,
Ci_4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 haloalkylthio,
C(H)=N-OH, C(H)=N-0(Ci_ 6 alkyl), C(C 1-6 alkyl)=N-OH and
C(Ci_6 alkyl)=N-0-(Ci_ 6 alkyl), and thienyl, which may itself be substituted by 1
to 3 substituents, each independently selected from halogen, cyano, nitro,
Ci_4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 haloalkylthio,
C(H)=N-OH, C(H)=N-0(Ci_ 6 alkyl), C(C 1-6 alkyl)=N-OH and
C(Ci_6 alkyl)=N-0-(Ci_6 alkyl) ;
or R6 is a 5-6 membered heterocyclic ring, wherein the heterocyclic ring contains
1 to 3 heteroatoms, each heteroatom independently chosen from oxygen, sulphur
and nitrogen, wherein the heterocyclic ring may be substituted 1
to 3 substituents, each independently selected from halogen, cyano, nitro,
Ci_4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 alkylthio, Ci_4alkylthio,
C haloalkoxy, C(H)=N-0-(Ci_ 6 alkyl) and C(Ci_6 alkyl)=N-0-(Ci_ 6 alkyl),
C2-5 alkenyl, C2-5 alkynyl, CHO, COOCi-C 6 alkyl, CrC4 alkoxy-Ci-C 4 alkyl,
CrC4 haloalkoxy-Ci-C 4 alkyl, (Z)PCºCR, (Z) CR28 =CR26 R27, phenyl, which
may itself be substituted by 1 to 3 substituents, each independently selected from
halogen, cyano, nitro, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy,
C haloalkylthio, C(H)=N-OH, C(H)=N-0(Ci_ 6 alkyl), C(C 1-6 alkyl)=N-OH
and C(Ci_6 alkyl)=N-0-(C 1-6 alkyl), and thienyl, which may itself be substituted
by 1 to 3 substituents, each independently selected from halogen, cyano, nitro,
Ci-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 haloalkylthio,
C(H)=N-OH, C(H)=N-0(Ci_ 6 alkyl), C(C 1-6 alkyl)=N-OH and
C(Ci_6 alkyl)=N-0-(Ci_ 6 alkyl), and wherein two substituents on adjacent carbon
atoms of the 5-6 membered heterocyclic ring together may form a group
-CR6a -CR6a =CR6a -CR6a -, wherein each R6a independently is selected from
hydrogen, halogen, cyano, nitro, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy,
Ci-4 haloalkoxy, C 1-4 haloalkylthio, C(H)=N-OH, C(H)=N-0(C 1-6 alkyl),
C(Ci_6 alkyl)=N-OH and C(C 1-6 alkyl)=N-0-(Ci_ 6 alkyl) ;
or R6 is an aliphatic saturated or unsaturated group containing 3 to 13 carbon
atoms and at least one silicon atom, wherein the aliphatic group may contain 1
to 3 heteroatoms, each heteroatom independently selected from oxygen, nitrogen
and sulphur, and wherein the aliphatic group may be substituted by 1 to 4
independently selected halogen atoms ;
or R6 is (CRa R )m-Cy-(CR Rd) -Yi ;
or R6 is Ci-6 alkoxy, C1-6 haloalkoxy, C2-6 alkenyloxy, C2-6 haloalkenyloxy,
C2-6 alkinyloxy, C3 6 cycloalkyloxy, C1-4 alkyl-C 3_7 cycloalkyloxy,
C 5-7 cyclo alkenyloxy or C1-4 alkyl-Cs-7 cycloalkenyloxy ;
Z is Ci-4 alkylene ;
p is 0 or 1 ;
25 R is hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy (C1-4) alkyl,
Ci-4 haloalkoxy (C1-4) alkyl or Si(C 1-4 alkyl) 3 ;
R26 and R27 are each, independently, hydrogen, halogen, C1-4 alkyl or
Ci-4 haloalkyl ;
R25 is hydrogen, C1-4 alkyl or C1-4 haloalkyl ;
Ra, R , R and Rd are each, independently, hydrogen or a C1-4 alkyl group, which
may substituted by 1 to 6 substituents, each substituent independently selected
from halogen, hydroxy, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl,
methoxy, ethoxy, methylsulfonyl, ethylsulfonyl, difluoromethoxy,
trifluoromethoxy, trifluoromethylthio and trifluorothiomethoxy ;
Cy is a carbocyclic or heterocyclic 3-7 membered ring, which may be saturated,
unsaturated or aromatic and which may contain a silicon atom as a ring member,
wherein (CR R )m and (CR Rd) may be bound either to the same carbon or
silicon atom of Cy or to different atoms separated by 1, 2 or 3 ring members,
wherein the carbocyclic or heterocyclic 3-7 membered ring may substituted by 1
to 6 substituents, each substituent independently selected from halogen,
Ci-4 alkyl, C2-4 alkenyl, C1-4 haloalkyl, Ci_4alkoxy and halo-Ci_4 alkoxy ;
Yi is Si(O 1 2 3 piZ )(OqZ )(0 £Z ) and provided that Cy contains a silicon atom as a
ring member then Yi may also be hydrogen ;
Z1 and Z2 are independently methyl or ethyl ;
Z is a Ci_4 alkyl or a C2_4 alkenyl group, which may be interrupted by one
heteroatom selected from O, S and N, and wherein the Ci_4 alkyl or C2_4 alkenyl
group may be substituted by 1 to 3 independently selected halogen atoms ;
m and n are each independently 0, 1, 2 or 3 ;
i, q and s are each independently 0 or 1 ;
R7, R8, R9, R10 , R11, R12 and R12a are each, independently, hydrogen, halogen,
cyano, nitro, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy,
Ci_4 thioalkyl or C1-4 thiohaloalkyl ;
R1 , R14 , R15 , R16 and R17 are each, independently, hydrogen, halogen, cyano,
nitro, C - alkyl, C(0)CH 3 C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy,
Ci_4 thioalkyl, C1-4 thiohaloalkyl, hydroxymethyl or C1-4 alkoxymethyl ;
W is a single or a double bond ; and
Y is O, N(R 18 ), S or (CR1 R20)(CR2 1R22 )mi(CR2 R24) ;
R18 is hydrogen, C1-4 alkyl, formyl, C1-4 alkoxy(Ci_4)alkyl, C(=0)C 1-4 alkyl,
which may be substituted by halogen or Ci_4-alkoxy, or C(=0)0-C 1-6 alkyl,
which may be substituted by halogen, C1-4 alkoxy or CN ;
R19 , R20, R2 1, R22 , R23 and R24 are each independently hydrogen, halogen,
hydroxy, C1-4 alkoxy, C1-6 alkyl, which may be substituted by 1 to 3 substituents
selected from halogen, hydroxy, =0, C1-4 alkoxy, 0-C(0)-C 1-4 alkyl, phenyl,
naphthyl, anthracyl, fluorenyl, indanyl or a 3-7 membered carbocyclic ring
(which itself may be substituted by 1 to 3 methyl groups), C1-6 alkenyl, which
may be substituted by 1 to 3 substituents selected from halogen, hydroxy, =0,
Ci_4 alkoxy, 0-C(0)-C 1-4 alkyl, phenyl, naphthyl, anthracyl, fluorenyl, indanyl or
a 3-7 membered carbocyclic ring (which itself may be substituted by 1
to 3 methyl groups), or a 3- 7 membered carbocyclic ring, which may contain 1
heteroatom selected from nitrogen and oxygen, and wherein the 3-7 membered
carbocyclic ring may be substituted by 1 to 3 methyl groups ;
or R19 , R20 together with the carbon atom to which they are attached form a
carbonyl-group, a 3-5 membered carbocyclic ring, which may be substituted by 1
to 3 methyl groups, C1-6 alkylidene, which may be substituted by 1 to 3 methyl
groups, or C3 6 cycloalkylidene, which may be substituted by 1 to 3 methyl
groups ;
mi is 0 or 1 ;
ni is 0 or 1 ;
R1 is a C 1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl group, which may be
substituted by 1 to 6 substituents, each substituent independently selected from
halogen, hydroxy, cyano, C1-4 alkoxycarbonyl, formyl, nitro, C 1-C4 alkoxy,
C 1-C4 haloalkoxy, C 1-C4 alkylthio, C 1-C4 haloalkylthio, HC(OR 2 )=Nand
R 0R 1NN=C(H)- ;
R29, R30 and R31 independently of one another are hydrogen or C 1-C4 alkyl ;
R1 is a Ci-C 6 alkyl group, which may be substituted by 1 to 6 substituents, each
substituent independently selected from halogen, hydroxy, cyano,
Ci-4 alkoxycarbonyl, formyl, nitro, C 1-C4 alkoxy, C 1-C4 haloalkoxy,
C 1-C4 alkylthio, C 1-C4 haloalkylthio, HC(OR 2)=N- and R R 4NN=C(H)- ;
R32, R33 and R24 independently of one another are hydrogen or C 1-C4 alkyl ;
R1 is hydrogen or halogen ; and tautomers/isomers/enantiomers of these
compounds
which comprises reacting a compound of formula (II)
wherein :
- Rl is an organic residue
R2 and R3 are as defined above, with an amine of formula (III) :
QNHR4 (III) wherein Q is as defined above, in the presence of a Lewis acid.
It has been found, surprisingly, that when a compound of formula (II) and
an amine of formula (III) are reacted in the presence of a Lewis acid comprising
at least one halogen ligand, a highly efficient production of the desired
carboxamide of formula (I) is obtained. The Lewis acid for use in this invention
is now explained.
The Lewis acid acid comprising at least one halogen ligand, which serves
as an electron acceptor, usually comprises a typical element, such as boron,
aluminum, silicon, or tin, or a transition metal element belonging to the fourth
period, such as titanium, iron, nickel, copper, or zinc, as the central element.
Aluminum as central element is preferred.
At least one ligand of the Lewis acid central element is a halogen ligand
such as chloride, bromide, iodida or fluoride, wherein chloride and fluoride are
preferred. In a preferred aspect, all ligands are halogen ligands of the same or
different species; more preferred are Lewis acids wherein the ligands are of the
same ligand species, such as a trichloro- or trifluoro Lewis acid. If not all ligands
are halogen ligands, the one or more remaining ligands can be, for example, ions
of an alkoxide such as an ethoxide, propoxide, or butoxide, or alkyl groups, such
as methyl, ethyl, n-propyl, i-propyl and all isomeric forms of butyl; methyl is
preferred. Such Lewis acids, specifically A1C13 and BF3are well known in the art
and commercially available. In the case of using a Lewis acid having two or
more kinds of ligands, such a Lewis acid may be prepared beforehand or may be
synthesized in situ through exchange reaction by a well-known method
(see Kaoru Fuji and Manabu Noide, Yuki Gosei Kagaku (Organic Synthesis
Chemistry), 42, 194 (1984)).
Specific examples of the Lewis acid for use in this invention include boron
trihalides such as boron trifluoride, boron trichloride, and boron tribromide,
aluminum trihalides such as aluminum chloride and aluminum bromide, tin
tetrahalides such as tin tetrachloride, tin dihalides such as tin dichloride, titanium
tetrahalides such as titanium tetrachloride, titanium trihalides such as titanium
trichloride, titanium alkoxides such as titanium isopropoxide, iron dihalides such
as iron dichloride, iron trihalides such as iron trichloride, nickel dihalides such as
nickel dichloride, and zinc halides such as zinc chloride and zinc bromide.
More preferred Lewis acids are boron trihalides, aluminum trihalides, tin
tetrahalides, titanium tetrahalides, titanium alkoxides, iron trihalides, and zinc
halides. Further preferred of these are iron trichloride, aluminum chloride,
titanium isopropoxide, titanium tetrachloride, and zinc chloride, with aluminum
chloride being the most preferred, especially for the process according to the
second embodiment.
In the first embodiment of the process according to the present invention,
the process is carried out in such a way that the Lewis acid is used in an amount
equal to or greater than 0.25 equivalents, per mol compound of formula (II).
Preferably this amount is equal to or greater than 0.5 equivalents, more
preferably equal to or greater than 0,75 equivalents, even more preferably equal
to or greater than 1 equivalents, and most preferably equal to or greater
than 1,1 equivalents per mol compound of formula (II). Generally, the Lewis
acid is used in an amount equal to or smaller than 4 equivalents, per mol
compound of formula (II). Preferably this amount is equal to or smaller than 3
equivalents, more preferably equal to or smaller than 2.5 equivalents, even more
preferably equal to or smaller than 2 equivalents, and most preferably equal to or
smaller than 1.5 equivalents per mol compound of formula (II). In a second
embodiment according to the present invention, the reaction is further carried out
in the presence of an additional base which is different from the compound
according to formula (III). In one aspect of this embodiment, the process is
carried out in such a way that the Lewis acid is generally used in an amount
equal to or greater than 0.25 equivalents, per mol ester of formula (II).
Preferably this amount is equal to or greater than 0.5 equivalents, more
preferably equal to or greater than 1.0 equivalents, even more preferably equal to
or greater than 1.5 equivalents, and most preferably equal to or greater
than 3 equivalents per mol ester of formula (II). Generally, the Lewis acid is
used in an amount equal to or smaller than 8 equivalents, per mol ester of
formula (II). Preferably this amount is equal to or smaller than 7 equivalents,
more preferably equal to or smaller than 6 equivalents, even more preferably
equal to or smaller than 5 equivalents, and most preferably equal to or smaller
than 4 equivalents per mol ester of formula (II). In one aspect of this
embodiment, the additional base is generally used in an amount equal to or
greater than 0.05 equivalents, per mol Lewis acid. Preferably this amount is
equal to or greater than 0.1 equivalents, more preferably equal to or greater than
0.15 equivalents, even more preferably equal to or greater than 0.2 equivalents,
and most preferably equal to or greater than 0.25 equivalents per mol Lewis acid.
Generally, the additional base is used in an amount equal to or smaller than 2
equivalents, per mol Lewis acid. Preferably this amount is equal to or smaller
than 1.9 equivalents, more preferably equal to or smaller than 1.8 equivalents,
even more preferably equal to or smaller than 1.7 equivalents, and most
preferably equal to or smaller than 1.5 equivalents per mol Lewis acid. In one
aspect of the second embodiment, the preferred Lewis acid is an aluminum or
boron trihalide, in particular aluminum trichloride.
The term "additional base" preferably intends to denote a nucleophilic
base. In another aspect, the term "additional base" intends to denote a
non-nucleophilic base.
For the purpose of the present invention, the term "nucleophilic base"
denotes a base which is capable to function as a nucleophile. Preferred
nucleophilic bases are primary, secondary and tertiary amines, such as
diethylamine, triethylamine, methylpiperidine and N-methylmorpholine, wherein
triethylamine is the preferred base.
For the purpose of the present invention, the term "non-nucleophilic base"
denotes a base which is at the same time a poor nucleophile.
Examples of suitable non-nucleophilic bases include sterically hindered
alcoholates, such as potassium tert-butoxide (KOtBu), sodium tertbutoxide
(NaOtBu) ; amines such as DBU (l,8-diazabicyclo[5.4.0]undec-7-ene),
DBN (l,5-Diazabicyclo[4.3.0]non-5-ene), TMG (tetramethylguanidine),
TBD (triazabicyclodecene) ; lithium compounds such as lithium
diisopropylamide (LDA), tert-Butyllithium (tBuLi), lithium
tetramethylpiperidide (Li-TMP) ; silicium compounds such as Sodium
hexamethyldisilazane (Na-HMDS), Potassium hexamethyldisilazane (K-HMDS).
Aluminium compounds such trimethyl aluminium. From among those,
potassium tert-butoxide, trimethyl aluminium LDA, and DBU are more
preferred. Most preferred base is potassium tert-butoxide.
If desired, the base may be an environmental friendly base which is for
example prepared via a ring opening reaction of b or g-lactones.
It has been found, in the first embodiment, that controlling the amount of
the Lewis acid in the reaction medium improves the efficiency of the process and
the yield and purity of the desired carboxamide of formula (I). In the second
embodiment, controlling the amount of the Lewis acid and base in the reaction
medium has been found to improve the efficiency of the process and the yield
and purity of the desired carboxamide of formula (I). According to the second
embodiment, the term "additional base" intends to denote a base that is not
identical with the compound of formula (III). In a third embodiment, the
compound of formula (III) is used in an excess of equal to or more
than 1.2 molar equivalents, more preferably of equal to or more than 1.3, and
even more preferably of equal to or more than 1.4 molar equivalents molar
equivalents, with respect of the compound of formula (II), making the use of an
additional base unnecessary. In another aspect of the invention, the addition of a
base which is not identical with the compound of formula (III) can be
advantageous even if the compound of formula (III) is used in an excess of more
than 1.2 mol equivalents with respect to the amount of compound of formula (II).
The invention will be further described in more detail and the definitions
and preferences described below for the compounds including starting
compounds and target compounds and process conditions related to the process
according to the invention equally apply to the first, second and third
embodiment, indicated above and further embodiments, described below, of the
process according to the invention.
The term "organic residue" is intended to denote in particular linear or
branched alkyl or alkylene groups which may contain hetero atoms, such as in
particular boron, silicon, nitrogen, oxygen or sulphur atoms and halogen atoms,
cycloalkyl groups, heterocycles and aromatic systems. The organic residue may
contain double or triple bonds and functional groups.
The organic residue comprises at least 1 carbon atom. It often comprises at
least 2 carbon atoms. It preferably comprises at least 3 carbon atoms. More
particularly preferably, it comprises at least 5 carbon atoms.
The organic residue generally comprises at most 100 carbon atoms. It
often comprises at most 50 carbon atoms. It preferably comprises at most
40 carbon atoms. More particularly preferably, it comprises at most
30 carbon atoms.
Rl is typically selected from the group consisting of H, linear or branched
alkyl or alkylene groups, cycloalkyl or cycloalkylene groups, heterocycles and
aromatic systems, optionally containing heteroatoms, double bonds, triple bonds,
functional groups and mixtures thereof. In a preferred aspect, Rl is selected
from the group consisting of H, linear or branched alkyl or alkylene groups,
cycloalkyl or cycloalkylene groups, heterocycles and aromatic systems,
optionally containing heteroatoms, double bonds, triple bonds, functional groups
and mixtures thereof ; preferably from H, Ci-Cs-alkyl, Ci-Cs-haloalkyl
C3-C8-cycloalkyl, C1-C4 alkoxy-Ci-C4 alkyl, C3-C cycloalkoxy-Ci-C4 alkyl,
C Yl 2-C alkenyl, and benzyl optionally substituted by 1, 2 or 3 substituents R
independently of one another selected from Ci-C 4 alkyl, Ci-C 4 alkoxy and nitro ;
more preferably from H, Ci-C 4-alkyl, Ci-C 4-haloalkyl, and benzyl; most
preferably from methyl, ethyl, trifluoroethyl, pentafluoropropyl, hexafluoro-isopropyl,
n-propyl, and isopropyl ; most preferably ethyl.
R2 is usually selected from the group consisting of H, and an organic
residue selected from the group consisting of linear or branched alkyl or alkylene
groups, cycloalkyl or cycloalkylene groups, heterocycles and aromatic systems,
optionally containing heteroatoms, double bonds, triple bonds, functional groups
and mixtures thereof. In a preferred aspect, R2 is selected from the group
consisting of H, and an organic residue selected from the group consisting of
linear or branched alkyl or alkylene groups, cycloalkyl or cycloalkylene groups,
heterocycles and aromatic systems, optionally containing heteroatoms, double
bonds, triple bonds, functional groups and mixtures thereof ; preferably from H,
C1-C4 alkyl, benzyl and phenyl, where benzyl and phenyl may be optionally
substituted by 1, 2 or 3 substituents RY2 independently of one another selected
from halogen, nitrile, nitro, Ci-C 4-alkyl, Ci-C 4-haloalkyl, Ci-C 4-alkoxy and Ci-
C4-haloalkoxy ; more preferably from H and Ci-C 4-alkyl ; most preferably
methyl.
The term "aliphatic" intends to denote an acyclic or cyclic, saturated or
unsaturated carbon compound, for example an alkyl group, cycloalkyl, alkylene,
a halogenated alkyl group. A cyclic aliphatic, also denoted alicyclic, group has a
carbocyclic ring structure which may be saturated or unsaturated, but may not be
a benzenoid or other aromatic system. The term "aliphatic" comprises, for
example, the term "alkyl group", "cycloalkyl group", "alkylene group" or
"cycloalkylene group, or "halogenated alkyl group".
The term "heteroaliphatic" intends to denote an aliphatic group as defined
above further comprising heteroatoms. A cyclic heteroaliphatic, also denoted
heterocyclic, group has a carbocyclic ring structure further comprising one or
more heteroatoms which may be saturated or unsaturated, but may not be an
aromatic system. The term "heteroaliphatic" comprises, for example, the term
"heterocycle".
The term "aromatic" typically intends to denote a carboxyclic, cyclically
conjugated molecular entity with a stability (due to derealization) significantly
greater than that of a hypothetical localized structure.
The term "heteroaromatic" typically intends to denote a heterocyclic,
cyclically conjugated molecular entity with a stability (due to derealization)
significantly greater than that of a hypothetical localized structure. The term
"alkyl group" is intended to denote in particular a linear or branched alkyl
substituent comprising from 1 to 20 carbon atoms, preferably 1, 2, 3, 4, 5, 6, 7, 8,
9 or 10 carbon atoms. Specific examples of such substituents are methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-hexyl,
2-hexyl, n-heptyl, n-octyl and benzyl.
The term "cycloalkyl group" is intended to denote in particular a
substituent comprising at least one saturated carbocycle containing 3
to 10 carbon atoms, preferably 5, 6 or 7 carbon atoms. Specific examples of
such substituents are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and
cycloheptyl.
The term "alkylene group" or "cycloalkylene group" is intended to denote
in particular the divalent radicals derived from the alkyl or cycloalkyl groups as
defined above.
When the organic residue contains one or optionally more double bonds, it
is often chosen from an alkenyl or cycloalkenyl group comprising from 2
to 20 carbon atoms, preferably 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific
examples of such groups are vinyl, 1-allyl, 2-allyl, n-but-2-enyl, isobutenyl,
1,3-butadienyl, cyclopentenyl, cyclohexenyl and styryl.
When the organic residue contains one or optionally more triple bonds, it is
often chosen from an alkinyl group comprising from 2 to 20 carbon atoms,
preferably 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. Specific examples of such
groups are ethinyl, 1-propinyl, 2-propinyl, n-but-2-inyl and 2-phenylethinyl.
When the organic residue contains one or optionally more aromatic
systems, it is often an aryl group comprising from 6 to 24 carbon atoms,
preferably from 6 to 12 carbon atoms. Specific examples of such groups are
phenyl, 1-tolyl, 2-tolyl, 3-tolyl, xylyl, 1-naphthyl and 2-naphthyl.
The term "heterocycle" is intended to denote in particular a cyclic system
comprising at least one saturated or unsaturated ring made up of 3, 4, 5, 6, 7
or 8 atoms, at least one of which is a hetero atom. The hetero atom is often
chosen from B, N, O, Si, P and S. It is more often chosen from N, O and S.
Specific examples of such heterocycles are aziridine, azetidine, pyrrolidine,
piperidine, morpholine, 1,2,3,4-tetrahydroquinoline,
1,2,3,4-tetrahydroisoquinoline, perhydroquinoline, perhydroisoquinoline,
isoxazolidine, pyrazoline, imidazoline, thiazoline, tetrahydrofuran,
tetrahydrothiophene, pyran, tetrahydropyran and dioxane.
The organic residues as defined above may be unsubstituted or substituted
with functional groups. The term "functional group" is intended to denote in
particular a substituent comprising or consisting of a hetero atom. The hetero
atom is often chosen from B, N, O, Al, Si, P, S, Sn, As and Se and the halogens.
It is more often chosen from N, O, S and P, in particular N, O and S.
The functional group generally comprises 1, 2, 3, 4, 5 or 6 atoms.
By way of functional groups, mention may, for example, be made of
halogens, a hydroxyl group, an alkoxy group, a mercapto group, an amino group,
a nitro group, a carbonyl group, an acyl group, an optionally esterified carboxyl
group, a carboxamide group, a urea group, a urethane group and the thiol
derivatives of the abovementioned groups containing a carbonyl group,
phosphine, phosphonate or phosphate groups, a sulphoxide group, a sulphone
group and a sulphonate group.
The term "halogenated alkyl group" is intended to denote in particular an
alkyl group comprising from 1 to 20 carbon atoms and at least one halogen,
preferably 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and at least one halogen.
Suitable halogenated alkyl groups are selected for example from chlorinated
alkyl groups such as chloromethyl, dichloromethyl, trichloromethyl,
1-chloroethyl or 2,2,2-trichloroethyl fluorinated alkyl groups such as
fluoromethyl, difluoromethyl, trifluoromethyl, 1 -fluoroethyl, 2-fluoroethyl,
2,2-difluoroethyl, 2,2,2-trifluoroethyl or pentafluoroethyl, chlorofluorinated alkyl
groups such as chlorofluoromethyl, dichlorofluoromethyl, chlorodifluoromethyl,
2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl or 2,2- dichloro-2-fluoroethyl,
brominated alkyl groups such as bromomethyl and 1-bromoethyl.
In a preferred embodiment of the process according to the invention, Rl
is -C8-alkyl, d-Q-haloalkyl, C3-C8-cycloalkyl, Ci-C4-alkoxy-Ci-C 4-alkyl,
C3-C8-cycloalkoxy-Ci-C 4-alkyl, C2-C8-alkenyl or is benzyl which is optionally
substituted by 1,2 or 3 substituents RYl independently of one another selected
from the group consisting of d-C 4-alkyl, d-C 4-alkoxy and nitro; and
R2 is hydrogen, Ci-C4-alkyl, benzyl or phenyl, where the two
last-mentioned substituents may be unsubstituted or optionally substituted
by 1,2 or 3 substituents RY2 independently of one another selected from the
group consisting of halogen, nitrile, nitro, d-C 4-alkyl, d-C 4-haloalkyl,
d-C 4-alkoxy and d-C 4-haloalkoxy; and
R3 is an alkyl group or a halogenated alkyl group. R is hydrogen,
Crd-alkyl, benzyl or phenyl.
The terms, used in the definition of the variables, for organic groups, such
as, for example, the term "halogen", are collective terms representing the
individual members of these groups of organic moieties.
The prefix Cx-Cy denotes the number of possible carbon atoms in the case
in question. Ci-C4-Alkyl includes, for example, methyl, ethyl, propyl,
1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl.
The term "halogen" denotes in each case fluorine, bromine, chlorine or
iodine, especially fluorine, chlorine or bromine. This also applies,
correspondingly, to halogen in combination with other meanings, such as
haloalkyl or haloalkoxy.
The term "alkoxy" is, for example, methoxy, ethoxy, propoxy, i-propoxy,
n-butoxy, isobutoxy, sec-butoxy and tert-butoxy ; preferably methoxy and
ethoxy.
Haloalkoxy is, for example, fluoromethoxy, difluoromethoxy,
trifluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy,
2-fluoroethoxy, 2-chloroethoxy, 2,2-difluoroethoxy and 2,2,2-trichloroethoxy ;
preferably difluoromethoxy, 2-chloroethoxy and trifluoromethoxy. Alkylthio is,
for example, methylthio, ethylthio, propylthio, isopropylthio, n-butylthio,
isobutylthio, sec-butylthio or tert-butylthio, preferably methylthio and ethylthio.
The term "Ci-C4-alkoxy -Ci-C4-alkyl", as used herein, describes
Ci-C4-alkyl radicals where one carbon atom is attached to a Ci-C4-alkoxy
radical. Examples of these are CH2-OCH 3, CH2-OC 2H5, n-propoxymethyl,
CH2-OCH(CH 3)2, n-butoxymethyl, (l-methylpropoxy)methyl,
(2-methylpropoxy)methyl, CH2-OC(CH 3)3, 2-(methoxy)ethyl, 2-(ethoxy)ethyl,
2-(n-propoxy)ethyl, 2-(l-methylethoxy)ethyl, 2-(n-butoxy)ethyl,
2-(l-methylpropoxy)ethyl, 2-(2-methylpropoxy)ethyl,
2-(l,l-dimethylethoxy)ethyl, 2-(methoxy)propyl, 2-(ethoxy)propyl,
2-(n-propoxy)propyl, 2-(l-methylethoxy)propyl, 2-(n-butoxy)propyl,
2-(l-methylpropoxy)propyl, 2-(2-methylpropoxy)propyl,
2-(l,l-dimethylethoxy)propyl, 3-(methoxy)propyl, 3-(ethoxy)propyl,
3-(n-propoxy)propyl, 3-(l-methylethoxy)propyl, 3-(n-butoxy)propyl,
3-(l-methylpropoxy)propyl, 3-(2-methylpropoxy)propyl,
3-(l,l-dimethylethoxy)propyl, 2-(methoxy) butyl, 2-(ethoxy)butyl,
2-(n-propoxy)butyl, 2-(l-methylethoxy)butyl, 2-(n-butoxy)butyl,
2-(l-methylpropoxy)butyl, 2-(2-methylpropoxy)butyl,
2-(l,l-dimethylethoxy)butyl, 3-(methoxy)butyl, 3-(ethoxy)butyl,
3-(n-propoxy)butyl, 3-(l-methylethoxy)butyl, 3-(n-butoxy)butyl,
3-(l-methylpropoxy)butyl, 3-(2-methylpropoxy)butyl,
3-(l,l-dimethylethoxy)butyl, 4-(methoxy)butyl, 4-(ethoxy)butyl,
4-(n-propoxy)butyl, 4-(l-methylethoxy)butyl, 4-(n-butoxy)butyl,
4-(l-methylpropoxy)butyl, 4-(2-methylpropoxy) butyl,
4-(1,1-dimethylethoxy)butyl.
The term "C2-C8 -alkenyl", as used herein, describes straight-chain and
branched unsaturated hydrocarbon radicals having 2 to 8 carbon atoms and at
least one carbon-carbon double bond, such as, for example, ethenyl, 1-propenyl,
2-propenyl, 1-methylethenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl- 1-
propenyl, 2-methyl- 1-propenyl, l-methyl-2-propenyl, 2-methyl-2-propenyl, 1-
pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl- 1-butenyl, 2-methyl- 1-
butenyl, 3-methyl- 1-butenyl, l-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-
2-butenyl, l-methyl-3-butenyl, 2-methyl-3-butenyl, 3-methyl-3-butenyl,
1,1-dimethyl-2-propenyl, 1,2-dimethyl- 1-propenyl, 1,2-dimethyl-2-propenyl,
1-ethyl- 1-propenyl, l-ethyl-2-propenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl,
4-hexenyl, 5-hexenyl, 1-methyl- 1-pentenyl, 2-methyl- 1-pentenyl, 3-methyl- 1-
pentenyl, 4-methyl- 1-pentenyl, l-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-
methyl-2-pentenyl, 4-methyl-2-pentenyl, l-methyl-3-pentenyl, 2-methyl-3-
pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl, l-methyl-4-pentenyl, 2-
methyl-4-pentenyl, 3-methyl-4-pentenyl, 4-methyl-4-pentenyl, l,l-dimethyl-2-
butenyl, l,l-dimethyl-3-butenyl, 1,2-dimethyl- 1-butenyl, l,2-dimethyl-2-
butenyl, l,2-dimethyl-3-butenyl, 1,3-dimethyl- 1-butenyl, l,3-dimethyl-2-
butenyl, l,3-dimethyl-3-butenyl, 2,2-dimethyl-3-butenyl, 2,3-dimethyl-lbutenyl,
2,3-dimethyl-2-butenyl, 2,3-dimethyl-3-butenyl, 3,3-dimethyl-lbutenyl,
3,3-dimethyl-2-butenyl, 1-ethyl- 1-butenyl, l-ethyl-2-butenyl, l-ethyl-3-
butenyl, 2-ethyl- 1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl, 1,1,2-trimethyl-
2-propenyl, 1-ethyl- l-methyl-2-propenyl, l-ethyl-2-methyl- 1-propenyl and
l-ethyl-2-methyl-2-propenyl, 1-heptenyl, 2-heptenyl, 1-octenyl or 2-octenyl.
In a preferred embodiment of the process according to the invention, X is
oxygen, Rl is Ci-C4-alkyl, Ci-C4-haloalkyl or benzyl, in particular methyl, ethyl,
trifluoroethyl, pentafluoropropyl, hexafluoro-iso-propyl,n-propyl or isopropyl ;
Rl is especially ethyl ; and
R2 is H or Ci-C4-alkyl ; R2 is especially methyl ; R3 is selected from a group
consisting of fluoromethyl, difluoromethyl, trifluoromethyl, chlorofluoromethyl,
dichlorofluoromethyl, and chlorodifluoromethyl ; R3 is especially
difluoromethyl. R4 is selected from the group consisting of hydrogen and
-C4-alkyl ; R4 is especially hydrogen ; Q is Ql or Q37.
In one embodiment, Q is Ql and R6 is a hydrogen, C1-12 alkyl, C2-12 alkenyl
or C2 12 alkynyl group, which may be substituted by 1 to 6 substituents, each
substituent independently selected from halogen, cyano, C1-4 alkoxy,
C thioalkyl, COO-Ci_4 alkyl, =N-OH, =N-0-(C1-4 alkyl), C3-8 cycloalkyl, which
may itself be substituted by 1 to 3 substituents, each independently selected from
Ci_4 alkyl, halogen, C1-4 alkoxy and C1-4 haloalkoxy, and C4_8 cycloalkenyl,
which may itself be substituted by 1 to 3 substituents, each independently
selected from C1-4 alkyl, halogen, C1-4 alkoxy and C1-4 haloalkoxy, R6 is
especially a hydrogen ; R7 , R8, R9 and R10 are each, independently, hydrogen,
halogen, C 7 8 9 1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, R , R , R
and R10 are especially each, independently, hydrogen and halogen, said halogen
is especially chlorine or fluorine.
In another embodiment, Q is Ql and R6 is phenyl, which may be
substituted by 1 to 3 substituents, each independently selected from halogen,
cyano, nitro, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 alkylthio,
Ci-4 haloalkoxy, C1-4 haloalkylthio, C(H)=N-OH, C(H)=N-0(C 1-6 alkyl),
C(Ci_6 alkyl)=N-OH, C(C 1-6 alkyl)=N-0-(Ci_ 6 alkyl), (Z)CºCR,
(Z) CR28 =CR26 R27, phenyl, which may itself be substituted by 1
to 3 substituents, each independently selected from halogen, cyano, nitro,
Ci-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 haloalkylthio,
C(H)=N-OH, C(H)=N-0(Ci_6 alkyl), C(C 1-6 alkyl)=N-OH and
C(Ci_6 alkyl)=N-0-(Ci_6 alkyl), and thienyl, which may itself be substituted by 1
to 3 substituents, each independently selected from halogen, cyano, nitro,
Ci-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 haloalkylthio,
C(H)=N-OH, C(H)=N-0(Ci_6 alkyl), C(C 1-6 alkyl)=N-OH and
C(Ci_6 alkyl)=N-0-(Ci_6 alkyl) ; R6 is especially phenyl, which is substituted in
the para-position by halogen, wherein said phenyl may be further substituted
by 1 to 2 substituents, each independently selected from halogen, C1-4 alkyl and
are especially each, independently, hydrogen
and halogen, said halogen is especially chlorine or fluorine.
In another embodiment, Q is Ql and R6 is a C3 8 cycloalkyl,
C4 - cycloalkenyl or C5-8 cycloalkadienyl group, which may be substituted by 1
to 3 substituents, each independently selected from halogen, Ci-4alkyl,
Ci-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 thioalkyl, C3 _6 cycloalkyl, which
may itself be substituted by 1 to 3 substituents, each independently selected from
Ci-4 alkyl, halogen, C1-4 alkoxy and C1-4 haloalkoxy, and phenyl, which may
itself be substituted by 1 to 5 independently selected halogen atoms ; R6 is
especially a C3 _8 cycloalkyl, which may be substituted by 1 to 3 substituents,
each independently selected from halogen, C1-4alkyl, C1-4 haloalkyl.
In another embodiment, Q is Q37 and R1 , R14 , R15 and R16 are each,
independently, hydrogen, halogen, C1-4 alkyl, C(0)CH 3 C1-4 haloalkyl,
Ci-4 alkoxy ; in particular R14 , R15 and R16 are each, independently, hydrogen,
methyl, methoxy or C(0)CH 3 ; R , R , R and R are especially each,
independently, hydrogen or methyl and W is a single bound ; and Y is O or
(CR 1 R20)(CR 2 1R22)mi(CR 2 R24) i ; preferably Y is
(CR 1 R20)(CR 2 1R22)mi(CR 2 R24) i, more preferably Y is (CR 1 R20)(CR 2 1R22)mi
and 1" , R20 , R2 1, R22 , 23 and R24 are each independently hydrogen, halogen,
Ci-4 alkoxy, Ci_6 alkyl, which may be substituted by 1 to 3 substituents selected
from halogen, hydroxy, =0, Ci_4 alkoxy, 0-C(0)-Ci_ 4 alkyl, phenyl, naphthyl,
anthracyl, fluorenyl, indanyl or a 3-7 membered carbocyclic ring (which itself
may be substituted by 1 to 3 methyl groups), Ci_6 alkenyl, which may be
substituted by 1 to 3 substituents selected from halogen, hydroxy, =0,
Ci_4 alkoxy, 0-C(0)-Ci_ 4 alkyl, phenyl, naphthyl, anthracyl, fluorenyl, indanyl or
a 3-7 membered carbocyclic ring (which itself may be substituted by 1
to 3 methyl groups), or a 3- 7 membered carbocyclic ring, which may contain
1 heteroatom selected from nitrogen and oxygen, and wherein the 3-7 membered
carbocyclic ring may be substituted by 1 to 3 methyl groups ; or R19 , R20 together
with the carbon atom to which they are attached form a carbonyl-group, a
3-5 membered carbocyclic ring, which may be substituted by 1 to 3 methyl
groups, Ci-6 alkylidene, which may be substituted by 1 to 3 methyl groups,
or C3 _6 cycloalkylidene, which may be substituted by 1 to 3 methyl groups ;
especially R19 and R20 together with the carbon atom to which they are attached
form a 3-membered or 5- membered carbocyclic ring ; preferably R2 1, R22 , R23
and R24 are each independently hydrogen or CH3.
In a first specific preferred embodiment, Q is a roup of formula Q39
(Q39)
wherein R' , R6b, R6c and R6 are each, independently, hydrogen or halogen, said
halogen is especially chlorine or fluorine.
In a second specific preferred embodiment, Q is a group of formula Q40
(Q40).
a third specific preferred e a group of formula Q41
(Q41).
In a particularly preferred aspect of the process of the present invention, an
amine of formula (III): QNHR4 (III) wherein Q is selected from a group
consisting of Q35 to Q41, is reacted with ethyl l-methyl-3-difluoromethylpyrazole-
4-carboxylate (DFMMP).
Amines of the formula (III) are either known, for example, from
EP 1490342, EP 0824099, EP 1480955 (Bl), WO 2004/035589,
WO 2007/031323, or they can be prepared according to generally known
methods.
In one particular embodiment of the present invention, the process
according to the present invention is comprised in a process for the manufacture
o pharmaceutically active or agrochemically active compounds or the
precursors. .Such a process can also comprise further processes or process steps.
The formation of the compound of formula (II) can be carried out, for
example, analogously to the reaction described in the patent applications
EP - 10170633.1 and EP - 10173899.5. The respective content of said patent
applications is incorporated by reference into the present patent application.
In the process according to the invention, the reaction is generally carried
out in an inert solvent. Examples of suitable inert solvents include hydrocarbons
such as benzene, toluene, xylene or cyclohexane; halogenated hydrocarbons such
as dichloromethane, trichloromethane or tetrachloromethane ; halogenated
aromatic hydrocarbons such as chlorobenzene, straight chain or cyclic ethers
such as diethyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl
ether, tetrahydrofuran or dioxane, nitriles such as acetonitrile or propionitrile,
amides such as N,N-dimethylformamide, diethylformamide or
N-methylpyrrolidinone ; these inert solvents can be used alone or in combination
as a mixture.
In a preferred specific embodiment, the solvent is selected from the group
consisting of halogenated hydrocarbons such as dichloromethane,
trichloromethane or tetrachloromethane; and straight chain or cyclic ethers such
as diethyl ether, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether,
tetrahydrofuran or dioxane. In a further specific embodiment, the solvent is
different than chlorobenzene, more particularly different than a halogenated
aromatic hydrocarbon.
The reaction is preferably carried out in a straight chain or cyclic ether, in
particular in a cyclic ether and particularly preferable in tetrahydrofuran (THF)
or dioxane.
Generally, an excess of the compound of formula (II) or (III) can also be
employed as solvent.
In a preferred aspect of the process of the present invention, the solvent is
substantially free of water.
For the purpose of the present invention, the term "solvent substantially
free of water" denotes in particular that the content of water in the solvent is
equal to or lower than 3100 mg/kg of water, preferably equal to or lower than
500 mg/kg of water, more preferably equal to or lower than 400 mg/kg of water,
most preferably equal to or lower than 50 mg/kg of water. The solvent can be
completely anhydrous. However, the solvent substantially free of water
generally contains at least 5 mg/kg of water, often at least 25 mg/kg of water.
Solvents which are substantially free of water allow shorter residence time
and/or lower temperatures thereby leading to a more economical and
environmental beneficial process.
If appropriate, the solvent is used usually in an amount of from 50 to 99 by
weight, preferably from 60 to 99 %by weight, more preferably from 75 to 99 %
by weight of the solvent relative to the total weight of the reaction medium.
The process according to the invention is, if appropriate, carried out in the
presence of a suitable phase transfer catalyst such as for example a crown ether.
This allows to increase the yield and to reduce the reaction time.
If desired, the solvent can be chosen on account of respective pKa of base
and reagents.
In the process according to the invention, the temperature of the reaction is
generally at least 0°C. The temperature of the reaction is often at least 15°C.
Preferably, this temperature is at least 25°C. The temperature of the reaction is
generally at most the boiling temperature of the solvent. Typically, the
temperature of the reaction is equal to or lower than 120°C, particularly equal to
or lower than 110°C, more particularly equal to or lower than 100°C,
most particularly equal to or lower than 90°C, a temperature equal to or lower
than 80°C being especially suitable. A temperature from 15 to 100°C is suitable,
a temperature from 15 to 90°C is particularly preferred, a temperature from 15
to 80°C is most particularly preferred.
Should the disclosure of any patents, patent applications, and publications
which are incorporated herein by reference conflict with the description of the
present application to the extent that it may render a term unclear, the present
description shall take precedence.
The following examples are intended to further explain the invention
without limiting it.
In these examples and throughout this specification the abbreviations
employed are defined as follows : DFMMP is ethyl l-methyl-3-difluoromethylpyrazole-
4-carboxylate. 2-(3,4,5-trifluorophenyl)aniline can be prepared, for
example, according to US201 1/301356. DFMMP, can, for example, be prepared
according to WO20 12/25469. 2-(bi(cyclopropan)-2-yl)benzenamine can, for
example, be prepared according to EP20 14642.
A mixture of 1.25 g (6.11 mmol, 1.0 eq) DFMMP and
1.50 g (6.73 mmol, 1.10 eq) 2-(3,4,5-trifluorophenyl)aniline is placed in a
flame-dried flask in mL dry dioxane. With stirring, 1,22 g (9.17 mmol, 1.5 eq)
of AICI 3 are added. The reaction is kept at 90°C for 3 h. The reaction mixture
is allowed to cool to room temperature over night, poured on water and
extracted with 200 ml ethyl acetate. The organic layer is washed with brine,
dried over Na2S0 4, and the solvent is removed in vacuum, giving 2.20 g crude
product as a brown solid. The solid is washed thoroughly with ethyl acetate,
yielding 1.70 g pure product as a light brown solid.
Evaporation of the mother liquor and column chromatography of the
residue on silica (w-hexanes/EE 2:1) yields further 100 mg for a total of 1.80 g
product (77 %).
HPLC/MS t : 12.6 min, [2M+Na] + 785, [M+Na] + 404, [M+H] + 382;
GC/MS t : 25.26 min, [M] + 381; 159; 1H-NMR (90 MHz, CDC13) : d (ppm) =
8.3-7.0 (m, 5H, Ar), 6.6 (t, 1H, CF2H), 3.9 (s, 3H, CH3)
Example 2 : Synthesis of Sedaxane ®
I To a solution of 2.93 g (14.3 mmol, 1.00 eq) DFMMP and 3.00 g
(17.3 mmol, 1.20 eq) 2-(bi(cyclopropan)-2-yl)benzenamine in 20 mL dry
dioxane, 10.0 ml (72.2 mmol, 5.40 eq) triethylamine was added, followed by
7.20 g (57.1 mmol, 4.00 eq) A1C13 which was added in one portion. After
stirring the reaction mixture for 1 h, it was cooled with ice and quenched with
water. The aqueous phase was extracted twice with ethyl acetate, the combined
organic layers were washed with water and brine, dried over Na2S0 4 and the
solvent removed under reduced pressure. The crude product was purified by
column chromatography (MTBEJ to yield (4.1 g, 85 ) Sedaxane ®.
HPLC: t, = 10.9 min + 11.4 min (trans +cis 62:38); HPLC/MS: t =
12.7 min [M+H] + 332; t = 13.3 min [M+H] + 332; NMR (500 MHz, CDC13)
d (ppm) = 8.46 (s, br, 0.35H), 8.08 (s, br, 0.65H), 8.26 (d, J = 8.2 Hz, 0.35H),
8.07 (d, J = 8.1 Hz, 0.65H), 7.98 (d, J = 6.3 Hz, 1H), 7.27-7.20 (m, 1H),
7.09-7.04 (m, 2H), 7.02-6.80 (m, 1H), 3.95 (s, 1H), 3.94 (s, 2H),
1.98-1.93 (m, 0.35H), 1.66-1.62 (m, 0.65H), 1.17-1.13 (m, 0.65H),
1.07-1.02 (m, 0.35H), 0.97-0.87 (m, 1H), 0.80-077 (m, 1H),
0.71-0.67 (m, 0.65H), 0.42-0.38 (m, 1.35H), 0.30-0.25 (m. 0.35H),
0.21-0.11 (m, 1.65H), 0.07-0.01 (m, 1H).

CLAIMS:
1. A process for the manufacture of compounds of formula (I)
(I)
wherein
- R2 is H or an organic residue
- R3 is H, an alkyl group having from 1 to 12 carbon atoms, a halogenated alkyl
group having from 1 to 12 carbon atoms, an aralkyl group, an aryl group, a
halogen
- R4 is H, an alkyl group having from 1 to 12 carbon atoms, a halogenated alkyl
group having from 1 to 12 carbon atoms, an aralkyl group, an aryl group, a
halogen
- X is oxygen or sulfur
- Q is a group of any of formulae (Ql) to (Q38) herein below:
(Q4) (Q5) (Q6)

wherein R6 is a hydrogen, Ci-12 alkyl, C2-12 alkenyl or C2-12 alkynyl group, which
may be substituted by 1 to 6 substituents, each substituent independently selected
from halogen, cyano, C1-4 alkoxy, Ci_4 thioalkyl, COO-Ci_4 alkyl, =N-OH,
=N-0-(Ci_4 alkyl), C3-8 cycloalkyl, which may itself be substituted by 1
to 3 substituents, each independently selected from Ci_4 alkyl, halogen,
Ci-4 alkoxy and C1-4 haloalkoxy, and C4_ cycloalkenyl, which may itself be
substituted by 1 to 3 substituents, each independently selected from C1-4 alkyl,
halogen, C1-4 alkoxy and C1-4 haloalkoxy ;
or R6 is a C3 8 cycloalkyl, C4_8 cycloalkenyl or C5-8 cycloalkadienyl group, which
may be substituted by 1 to 3 substituents, each independently selected from
halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 thioalkyl,
C3_6 cycloalkyl, which may itself be substituted by 1 to 3 substituents, each
independently selected from C1-4 alkyl, halogen, C1-4 alkoxy and C1-4 haloalkoxy,
and phenyl, which may itself be substituted by 1 to 5 independently selected
halogen atoms ;
or R6 is a C6-i2 bicycloalkyl, C6-i2 bicycloalkenyl or C6-i2 bicycloalkadienyl
group, which may be substituted by 1 to 3 substituents, each independently
selected from halogen, C1-4 alkyl and C1-4 haloalkyl ;
or R6 is phenyl, which may be substituted by 1 to 3 substituents, each
independently selected from halogen, cyano, nitro, C1-4 alkyl, C1-4 haloalkyl,
Ci_ alkoxy, C1-4 alkylthio, C1-4 haloalkoxy, C1-4 haloalkylthio, C(H)=N-OH,
C(H)=N-0(Ci_6 alkyl), C(C 1-6 alkyl)=N-OH, C(C 1-6 alkyl)=N-0-(Ci_ 6 alkyl),
(Z)CºCR, (Z) CR28 =CR26 R27 , phenyl, which may itself be substituted by 1
to 3 substituents, each independently selected from halogen, cyano, nitro,
C alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 haloalkylthio,
C(H)=N-OH, C(H)=N-0(Ci_6 alkyl), C(C 1-6 alkyl)=N-OH and
C(Ci_6 alkyl)=N-0-(Ci_6 alkyl), and thienyl, which may itself be substituted by 1
to 3 substituents, each independently selected from halogen, cyano, nitro,
Ci_4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 haloalkylthio,
C(H)=N-OH, C(H)=N-0(Ci_6 alkyl), C(C 1-6 alkyl)=N-OH
and C(Ci_6 alkyl)=N-0-(Ci_ 6 alkyl) ;
or R6 is a 5-6 membered heterocyclic ring, wherein the heterocyclic ring contains
1 to 3 heteroatoms, each heteroatom independently chosen from oxygen, sulphur
and nitrogen, wherein the heterocyclic ring may be substituted 1
to 3 substituents, each independently selected from halogen, cyano, nitro,
Ci_4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylthio,
C haloalkoxy, C(H)=N-0-(Ci_ 6 alkyl) and C(Ci_6 alkyl)=N-0-(Ci_ 6 alkyl),
C2-5 alkenyl, C2-5 alkynyl, CHO, COOCi-C 6 alkyl, Ci-C 4 alkoxy-Ci-C 4 alkyl,
C 1-C4 haloalkoxy-Ci-C 4 alkyl, (Z)PCºCR, (Z) CR =CR R , phenyl, which
may itself be substituted by 1 to 3 substituents, each independently selected from
halogen, cyano, nitro, Ci_4alkyl, Ci_4 haloalkyl, Ci_4 alkoxy, Ci_4 haloalkoxy,
C haloalkylthio, C(H)=N-OH, C(H)=N-0(Ci_ 6 alkyl), C(C 1-6 alkyl)=N-OH
and C(C 1-6 alkyl)=N-0-(Ci_ 6 alkyl), and thienyl, which may itself be substituted
by 1 to 3 substituents, each independently selected from halogen, cyano, nitro,
Ci_4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 haloalkylthio,
C(H)=N-OH, C(H)=N-0(Ci_ 6 alkyl), C(C 1-6 alkyl)=N-OH and
C(Ci_6 alkyl)=N-0-(Ci_ 6 alkyl), and wherein two substituents on adjacent carbon
atoms of the 5-6 membered heterocyclic ring together may form a group -CR 6
-CR6 =CR6 -CR6 -, wherein each R6 independently is selected from hydrogen,
halogen, cyano, nitro, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy,
C haloalkylthio, C(H)=N-OH, C(H)=N-0(Ci_ 6 alkyl), C(C 1-6 alkyl)=N-OH
and C(Ci_6 alkyl)=N-0-(Ci_ 6 alkyl) ;
or R6 is an aliphatic saturated or unsaturated group containing 3 to 13 carbon
atoms and at least one silicon atom, wherein the aliphatic group may contain 1
to 3 heteroatoms, each heteroatom independently selected from oxygen, nitrogen
and sulphur, and wherein the aliphatic group may be substituted by 1
to 4 independently selected halogen atoms ;
or R6 is (CRa R )m-Cy-(CR Rd) -Yi ;
or R6 is Ci- 6 alkoxy, C1-6 haloalkoxy, C2-6 alkenyloxy, C2-6 haloalkenyloxy,
C2-6 alkinyloxy, C 3-6 cycloalkyloxy, C1-4 alkyl-C3_7 cycloalkyloxy,
C 5-7 cyclo alkenyloxy or C1-4 alkyl-Cs-7 cycloalkenyloxy ;
Z is C1-4 alkylene ;
p is 0 or 1 ;
R25 is hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy(Ci_4)alkyl,
C1-4 haloalkoxy (C1-4) alkyl or Si(C 1-4 alkyl) 3 ;
R26 and R27 are each, independently, hydrogen, halogen, C1-4 alkyl or
C1-4 haloalkyl ;
R is hydrogen, C1-4 alkyl or C1-4 haloalkyl ;
Ra, R , R and Rd are each, independently, hydrogen or a C1-4 alkyl group, which
may substituted by 1 to 6 substituents, each substituent independently selected
from halogen, hydroxy, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl,
methoxy, ethoxy, methylsulfonyl, ethylsulfonyl, difluoromethoxy,
trifluoromethoxy, trifluoromethylthio and trifluorothiomethoxy ;
Cy is a carbocyclic or heterocyclic 3-7 membered ring, which may be saturated,
unsaturated or aromatic and which may contain a silicon atom as a ring member,
wherein (CR R )m and (CR Rd) may be bound either to the same carbon or
silicon atom of Cy or to different atoms separated by 1, 2 or 3 ring members,
wherein the carbocyclic or heterocyclic 3-7 membered ring may substituted by 1
to 6 substituents, each substituent independently selected from halogen,
Ci-4 alkyl, C2-4 alkenyl, C1-4 haloalkyl, Ci_4alkoxy and halo-Ci_4 alkoxy ;
Yi is Si(OpiZ1)(OqZ2)(0 £Z3) and provided that Cy contains a silicon atom as a
ring member then Yi may also be hydrogen ;
Z1 and Z2 are independently methyl or ethyl ;
Z is a Ci_4 alkyl or a C2_4 alkenyl group, which may be interrupted by one
heteroatom selected from O, S and N, and wherein the Ci_4 alkyl or C2_4 alkenyl
group may be substituted by 1 to 3 independently selected halogen atoms ;
m and n are each independently 0, 1, 2 or 3 ;
pi, q and s are each independently 0 or 1 ;
R7, R8, R9, R10 , R11, R12 and R12a are each, independently, hydrogen, halogen,
cyano, nitro, Ci_4 alkyl, Ci_4 haloalkyl, Ci_4 alkoxy, Ci_4 haloalkoxy,
Ci_4 thioalkyl or Ci_4 thiohaloalkyl ;
R1 , R14 , R15 , R16 and R17 are each, independently, hydrogen, halogen, cyano,
nitro, alkyl, C(0)CH 3 Ci_4 haloalkyl, Ci_4 alkoxy, Ci_4 haloalkoxy,
Ci_4 thioalkyl, Ci_4 thiohaloalkyl, hydroxymethyl or Ci_4 alkoxymethyl ;
W is a single or a double bond ; and
Y is O, N(R 18 ), S or (CR1 R20)(CR2 1R22)mi(CR2 R24 ) ;
R is hydrogen, C1-4 alkyl, formyl, C1-4 alkoxy(Ci-4) alkyl, C(=0)C 1-4 alkyl,
which may be substituted by halogen or C1-4 alkoxy, or C(=0)0-C 1-6 alkyl,
which may be substituted by halogen, C1-4 alkoxy or CN ;
R19 , R20, R2 1, R22 , R23 and R24 are each independently hydrogen, halogen,
hydroxy, C1-4 alkoxy, C1-6 alkyl, which may be substituted by 1 to 3 substituents
selected from halogen, hydroxy, =0, C1-4 alkoxy, 0-C(0)-C 1-4 alkyl, phenyl,
naphthyl, anthracyl, fluorenyl, indanyl or a 3-7 membered carbocyclic ring
(which itself may be substituted by 1 to 3 methyl groups), C1-6 alkenyl, which
may be substituted by 1 to 3 substituents selected from halogen, hydroxy, =0,
Ci_4 alkoxy, 0-C(0)-C 1-4 alkyl, phenyl, naphthyl, anthracyl, fluorenyl, indanyl or
a 3-7 membered carbocyclic ring (which itself may be substituted by 1
to 3 methyl groups), or a 3- 7 membered carbocyclic ring, which may contain
1 heteroatom selected from nitrogen and oxygen, and wherein the 3-7 membered
carbocyclic ring may be substituted by 1 to 3 methyl groups ;
or R19 , R20 together with the carbon atom to which they are attached form a
carbonyl-group, a 3-5 membered carbocyclic ring, which may be substituted by 1
to 3 methyl groups, C1-6 alkylidene, which may be substituted by 1 to 3 methyl
groups, or C3 6 cycloalkylidene, which may be substituted by 1 to 3 methyl
groups ;
mi is 0 or 1 ;
ni is 0 or 1 ;
R1 is a Ci-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl group, which may be
substituted by 1 to 6 substituents, each substituent independently selected from
halogen, hydroxy, cyano, C1-4 alkoxycarbonyl, formyl, nitro, Ci-C4 alkoxy,
Ci-C4 haloalkoxy, Ci-C4 alkylthio, - C4 haloalkylthio, HC(OR2 )=Nand
R 0R 1NN=C(H)- ;
R^29, R30 and R3 1 independently of one another are hydrogen or Ci-C4 alkyl ;
R1 is a Ci-C6 alkyl group, which may be substituted by 1 to 6 substituents, each
substituent independently selected from halogen, hydroxy, cyano,
Ci_4 alkoxycarbonyl, formyl, nitro, Ci-C4 alkoxy, Ci-C4 haloalkoxy,
Ci-C4 alkylthio, d - C4 haloalkylthio, HC(OR 2)=N- and R R 4NN=C(H)- ;
R , R and R independently of one another are hydrogen or C1-C4 alkyl ;
R1 is hydrogen or halogen ; and tautomers/isomers/enantiomers of these
compounds
which comprises reacting a compound of formula (II)
(P)
wherein
- Rl is an organic residue
- R2 and R3 are as defined above,
with an amine of formula (III) : QNHR4 (III) wherein Q and R4 are as defined
above, in the presence of a Lewis acid comprising at least one halogen ligand.
2. The process according to claim 1, wherein the process is further
carried out in the presence of an additional base which is different from the
compound according to formula (III).
3. The process according claim 1 or 2, wherein the Lewis acid
comprising at least one halogen ligand is selected from a group consisting of
aluminium compounds and boron compounds, in particular aluminium halides
and boron halides, more particularly aluminium trichloride and boron trichloride.
4. The process according to any one of claims 2 to 4, wherein the
additional base is a nucleophilic base, in particular wherein the nucleophilic base
is selected from the group consisting of diethylamine, triethylamine,
methylpiperidine and N-methylmorpholine, wherein triethylamine is the most
preferred nucleophilic base.
5. The process according to claim 1 or 3, wherein the Lewis acid is
present in an amount of from 0.25 to 4 molar equivalents relative to the amount
of the compound of formula (II), preferably in an amount of from 0.75 to 2 molar
equivalents relative to the amount of the compound of formula (II).
6. The process according to anyone of claims 2 to 4, wherein the Lewis
acid is present in an amount of from 0.25 to 8 molar equivalents relative to the
amount of the compound of formula (II), preferably in an amount of from 1 to 6
molar equivalents relative to the amount of the compound of formula (II).
7. The process according to anyone of claims 2, 3, 4 and 6, wherein the
additional base is present in an amount of from 0.25 to 8 molar equivalents
relative to the amount of the Lewis acid, preferably in an amount of from 1 to 6
molar equivalents relative to the amount of the Lewis acid.
8. The process according to any one of claims 1 to 7, wherein the
reaction is carried out in an inert solvent selected from a group consisting of
hydrocarbons, halogenated hydrocarbons, halogenated aromatic hydrocarbons,
straight chain or cyclic ethers, or nitriles; preferably from halogenated
hydrocarbons and straight chain or cyclic ethers; more preferably from straight
chain or cyclic ethers.
9. The process according to claim 8, wherein the inert solvent is a cyclic
ether, preferably dioxane.
10. The process according to any one of claims 1 to 9, wherein R3 is an
alkyl group or a halogenated alkyl group ; preferably a fluorinated alkyl group
selected from the group consisting of fluoromethyl, difluoromethyl,
trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl, and
chlorodifluoromethyl ; more preferably difluoromethyl.
11. The process according to anyone of claims 1 to 10, wherein R4 is
selected from the group consisting of H, Ci-Cs-alkyl, benzyl and phenyl ; in
particular H, Ci-C4-alkyl and benzyl ; more particularly from H, methyl, ethyl,
isopropyl and benzyl ; especially H.
12. The process according to any one of claims 1 to 11, wherein Q is a
group of formula Ql or Q37.
13. The process according to any one of claims 1 to 11, wherein Q is a
group of formula Q39
(Q39)
wherein R' , R6b, R6c and R6 are each, independently, hydrogen or halogen, said
halogen is especially chlorine or fluorine.
14. The process according to any one of claims 1 to 11, Q is a group of
formula Q40
(Q40).
15. The process according to any one of claims 1 to 11, Q is a group of
formula Q41
(Q41).
6. A process for the manufacture of pharmaceutically active or
agrochemically active compounds or their precursors, comprising at least the
process according to any one of claims 1to 15.