Process for the preparation of esters of l-substituted-3-fluoroalkylpyrazole-
4-carboxylic acids
The present application claims the benefit of the European application
no. 10170633.1 filed on July 23, 2010, herein incorporated by reference.
The invention concerns a process for the manufacture of esters of
l-substituted-3-fluoroalkyl-pyrazole-4-carboxylic acid, in particular esters of
3-difluorom ethyl- 1-methyl- lH-pyrazole-4-carboxylic acid, which are useful
e.g. as intermediates for pharmaceuticals and agrochemicals. Moreover, the
invention also relates to a process for the synthesis of substituted 3-chloro
fluoroalkyl -pyrazole-4-carboxylic acid esters, in particular esters of
3-chlorofluoromethyl-1 -methyl- lH-pyrazole-4-carboxylic acid.
US patent 5,498,624 describes the preparation of 3-difluorom ethyl- 1-
methyl- lH-pyrazole-4-carboxylic acid derivatives which are intermediates for
the manufacture of pyrazole carboxanilide fungicides.
WO 2008/053043 discloses a process for the synthesis of difluoromethyl -
substituted-pyrazole-4-carboxylic acid esters. The synthesis is carried out by
reacting 4,4,4-trihalogen-substituted acetoacetic ester derivatives with
chlorosilanes in the presence of magnesium or other metals of the 1st, 2nd, 3rd,
4th or 12th group of the Periodic Table of the Elements and subsequent reaction
of the reaction product with a hydrazine or hydrazine derivative.
It is an object of the present invention to provide a process for the synthesis
of esters of l-substituted-3-fluoroalkyl-pyrazole-4-carboxylic acid which allows
for high efficiency, and, in particular, high selectivity and for an environmental
beneficial process. The process according to the invention also allows the
utilization of starting materials (e.g.chlorodifluoroacetyl chloride (CDFAC))
which are available in industrial scale.
The invention consequently relates to a process for the manufacture of an
ester of a l-substituted-3-fluoroalkyl-pyrazole-4-carboxylic acid of formula (I)
(I)
wherein
- Y is H, F or an alkyl group having from 1 to 12 carbon atoms which is
optionally substituted by at least one halogen atom, an aralkyl group or
aryl group ;
- Ri is H or an organic residue,
- R2 is H or an organic residue,
which comprises submitting a compound of formula (II)
wherein Y is as defined above
- X is CI, Br or I,
- Ri is H or an organic residue,
- R2 is H or an organic residue,
to a reduction reaction.
The term "ester" includes, for the sake of simplicity, the free acid. The
esters are preferred.
It should be noted that Ri can be identical to or different from Ri. Also
R2 can be identical to or different from R2. Ri and/or R2 are different from Ri
and R2 if Ri and/or R2 undergo a reduction reaction in the process according to
the invention. If reduction of the Ri and/or R2 occurs, the resulting Ri and R2
can be defined as the reduced groups of Ri and/or R2 respectively.
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 or cycloalkylene 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.
Ri 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.
R2 is usually 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.
Ri' is generally 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.
R2' is most often 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.
The term "alkyl group" as given in the definition of organic residue 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 group comprising from 2 to 20 carbon atoms,
preferably 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms or a cycloalkenyl group
comprising from 3 to 20 carbon atoms, preferably 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.
In a preferred embodiment of the process according to the invention, Ri
is H, Ci-Cs-alkyl, C3-C -cycloalkyl, Ci-C4-alkoxy-Ci-C 4-alkyl,
C3-C -cycloalkoxy -Ci-C4 -alkyl, C2-C -alkenyl or is benzyl which is optionally
substituted by 1,2 or 3 substituents RY independently of one another selected
from the group consisting of Ci-C4-alkyl, Ci-C4-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, Ci-C4-alkyl, Ci-C4-haloalkyl, Ci-C4-alkoxy
and Ci-C4-haloalkoxy ; and
X is CI.
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-C 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.
The term "Ci-C4-alkoxy-Ci-C 4-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-OCH3, CH2-OC2H , n-propoxymethyl,
CH2-OCH(CH3)2, n-butoxymethyl, (l-methylpropoxy)methyl,
(2-methylpropoxy)methyl, CH2-OC(CH3)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 -methyl ethoxy)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-(l ,1-dimethylethoxy)butyl, etc.
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-lpentenyl,
4-methyl- 1-pentenyl, l-methyl-2-pentenyl, 2-methyl-2-pentenyl,
3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-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, 1,3-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, 1-ethyl-3-
butenyl, 2-ethyl-l-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, Ri is
H, Ci-C4-alkyl or benzyl, in particular methyl, ethyl, n-propyl or isopropyl ; Ri is
especially ethyl ; and
R2 is H or Ci-C4-alkyl. R2 is especially methyl ; X is CI and Y is F.
In the process according to the invention, the reduction reaction of the
compound of formula (II) can be carried out according to different reduction
reactions.
The reduction process according to the invention can comprise reacting the
compound of formula (II) with reducing agents such as LiAlH4, NaBH4,
diisobutylaluminium hydride (DIBAH), or phosphines, including PH3,
trialylphosphines (example : triisopropylphosphine) and triarylphosphines
(example : triphenylphosphine).
In a first embodiment, the reduction process according to the invention
comprises reacting the compound of formula (II) with zinc in the presence of an
alcohol. For example, the reaction can be performed as described in
WO 2005/085173 with metallic zinc. An alcohol is suitably present as proton
source. In one particular aspect, the alcohol is used as solvent for the reaction
with zinc. In another particular aspect, a mixture of alcohol and water is used as
solvent for the reaction.
In a second and preferred embodiment, the reduction process according to
the invention is a hydrogenation reaction comprising reacting the compound of
formula (II) with hydrogen, in particular hydrogen gas in the presence of a
hydrogenation catalyst. The use of hydrogen for said reduction reaction
advantageously avoids the formation of waste.
Surprisingly, it has been found that said hydrogenation is particularly
suitable for selectively substituting halogen, in particular chlorine atom, by a
hydrogen atom while the pyrazole ring remains substantially unaffected.
In this second embodiment of the process according to the invention, the
hydrogenation reaction is preferably carried out in the liquid phase. In this case,
the compound of formula (II) is advantageously dissolved in a solvent. Solvents
which can be used in the hydrogenation reaction are chosen, for example, from
polar solvents. In general, polar solvents comprising at least one OH group are
highly suitable. Examples of polar solvents comprising at least one OH group
may be selected from a group consisting of aliphatic alcohols preferably
comprising from 1 to 3 carbon atoms, water, organic acids such as acetic acid,
aqueous solutions of acids, preferably inorganic acids. Aliphatic alcohols
preferably comprising from 1 to 3 carbon atoms such as methanol, ethanol,
isopropanol (IPA) and the like are preferred. Polar aprotic solvents may also be
highly suitable, for instance tetrahydrofurane (THF), ethyl acetate, acetone,
dimethylformamide (DMF), acetonitrile or dimethylsulfoxide (DMSO),
especially THF. A single polar solvent can be used or a mixture of several polar
solvents.
The hydrogenation reaction is generally carried out in the presence of a
hydrogenation catalyst. The hydrogenation catalyst is advantageously chosen
from the metals from Group VIII of the Periodic Table of the Elements
(IUPAC 1970). Mention will be made in particular of a catalyst comprising at
least one metal chosen from nickel, palladium, platinum and rhodium. A catalyst
comprising nickel or palladium is preferred. Optionally, the reduction process
comprises substituting halogen, in particular chlorine atom by a hydrogen and
simultaneously hydrogenating of at least one of the unsaturated bonds in the
substituents Ri and/or R2 .
The hydrogenation catalyst is often a supported catalyst. Supports which
can be used are chosen, for example, from alumina, silica, titanium dioxide,
aluminium trifluoride, and carbon in particular active carbon or charcoal. A
catalyst supported on active carbon gives good results. An example of a suitable
catalyst comprises palladium on carbon support, often referred to as Pd/C, or
palladium hydroxide on carbon support, often referred to as Pd(OH) 2/C. Other
examples of suitable catalysts are for example palladium on alumina
support (Pd/Al20 3), rhodium on alumina (Rh/Al20 3), or Raney Nickel (RaNi).
When the hydrogenation catalyst is a supported catalyst comprising a metal
from Group VIII, the metal content is generally at least 0 .1% by weight with
respect to the total weight of the catalyst. The metal content is often greater than
or equal to 1% by weight. Preferably, the metal content is greater than or equal
to 5 % by weight. The metal content is generally at most 50 % by weight with
respect to the total weight of the catalyst. Typical amounts of metal are 0.5
to 20 % by weight of catalyst.
In a very particularly preferred way, the catalyst is supported palladium,
preferably supported on a support as described above, preferably exhibiting a
metal content as described above.
The hydrogenation catalyst is typically used in an amount of from 0 .1
to 50 mol % compared to 1 mol of compound of formula (II), particularly from
0.5 to 20 mol %, more particularly from 1 to 5mol %, for instance around 2, 3
or 4 mol %.
In the hydrogenation reaction, the temperature of the reaction is generally
at least -10°C. The temperature of the reaction is often at least 0°C. Preferably,
this temperature is at least 20°C, more preferably more than 25°C, most
preferably at least 40°C, for instance at least 60°C. The temperature of the
reaction is generally at most 160°C. The temperature of the reaction is often at
most 150°C. Preferably, this temperature is at most 130°C. A temperature of at
most 120°C, for instance at most 110°C, is very particularly preferred.
In the hydrogenation reaction, the pressure of the reaction is generally at
least 1 bar absolute. Preferably, the pressure is at least 1.5 bar. The pressure of
the hydrogenation reaction is generally at most 30 bar absolute. Preferably, the
pressure is at most 20 bar. In a particularly preferred way, it is at most 15 bar. A
pressure of lower than or equal to 10 bar is preferred. A pressure of about 5 bar
is very particularly preferred.
In a particular embodiment, the hydrogenation reaction is carried out at a
temperature from 0°C to 150°C and a pressure from 1 bar to 20 bar. Preferably
the hydrogenation reaction is carried out at a temperature from 20°C to 130°C
and a pressure from 1.5 bar to 10 bar. Most preferably, the hydrogenation
reaction is carried out at a temperature from 40°C to 120°C and a pressure from
1.5 bar to 10 bar.
In the process according to the invention, use is preferably made of
hydrogen gas as hydrogenation reactant. In this case, the pressure values of the
hydrogenation reaction mentioned above generally correspond to the hydrogen
pressure.
When use is made of hydrogen as hydrogenation reactant, the molar ratio
of hydrogen to the compound of formula (II) is generally greater than or equal
to 1. This ratio is generally at most 1000. Preferably, this ratio is at most 100.
More preferably, this ratio is at most 10.
In the hydrogenation reaction, the concentration of the compound of
formula II in the reaction medium is generally at least 5 % by weight with
respect to the total weight of the reaction medium. This concentration is often at
least 10 % by weight. Preferably, the concentration is at least 20 % by weight.
The concentration of the compound of formula II in the reaction medium is
generally at most 50 % by weight with respect to the total weight of the reaction
medium.
In the process according to the invention, the reduction reaction is
advantageously carried out in the presence of at least one additive, especially of
an organic base, an inorganic base or a salt, more particularly an inorganic base
or a salt. Organic bases are for instance amines or ammonium organic salts such
as ammonia, triethylamine or ammonium formiate, ammonium acetate
( H 4OAC), and sodium acetate (NaOAc). Inorganic bases can for instance be
selected from K2C0 3, Cs2C0 3, Na2C0 3, NaHC0 3, K3P0 4, NaOH, and KOH.
Salts may be selected from the group consisting of chlorides, fluorides, iodides
or Borax, for instance ammonium chloride ( H4C1), lithium chloride (LiCl), zinc
chloride (ZnCl 2), ammonium fluoride ( H4F), magnesium fluoride (MgF2),
lithium fluoride (LiF), aluminium fluoride (A1F3), cesium fluoride (CsF),
CsAlF 4, sodium iodide, or Borax (Na2B40 7.xH20). In the process of the present
invention, the additive may especially be selected from K2C0 3, H4C1, H4F,
CsF, Borax and mixtures thereof, preferably at least CsF.
Addition of at least one of said additives may be especially advantageous,
as it can lead to enhanced productivity and/or enhanced selectivity of the
hydrogenation reaction. It also allows performing the reaction at lower
temperature, compared to reaction in the absence of such additives.
Said additive is typically added in an amount of from 0.05 to 5 molar
equivalents of compound of formula (II), often from 0.1 to 3, more often from
0.5 to 2, for instance around 1.
An especially preferred first aspect of the second embodiment of the
present invention includes a hydrogenation reaction in the presence of Pd(OH) 2
and of at least an additive such as CsF, in particular in a polar aprotic solvent,
TUF being a suitable example.
An especially preferred second aspect of the second embodiment of the
present invention includes a hydrogenation reaction in the presence of supported
Pd, more particularly Pd/C, Pd/Ti0 2 or Pd/Al 20 3, most particularly Pd/C,
optionally in the presence of at least an additive such as CsF. Especially suitable
solvents for this preferred second aspect of the second embodiment of the
invention are polar aprotic solvents, for instance TUF.
An especially preferred third aspect of the second embodiment of the
present invention includes a hydrogenation reaction in the presence of Raney
Nickel in an aqueous solvent, especially H20 , in the presence of a base, more
preferably NH3.
The process according to the invention allows avoiding with particular
efficiency the saturation of the aromatic system of the pyrazole ring. The
process according to the invention can be used for the manufacture of industrial
amounts of esters of the l-substituted-3-fluoroalkyl-pyrazole-4-carboxylic acid
of formula (I).
According to the process of the present invention, compound of formula (I)
can for example be purified by distillation, especially by vacuum distillation.
Compound of formula (I) can also be purified by crystallization, for example
after dissolution in warm 1,1,1,3,3-pentafluorobutane (Solkane ®365 mfc)
followed by addition of n-hexane and further cooling of the medium.
In the process of the present invention, it is also possible to remove by
products corresponding to CFH 2- compounds rather than CF2H- compounds by
dismutation in presence of A1C13 powder. Such a dismutation reaction can for
example be performed in Solkane ®365 mfc at room temperature. Tthe reaction
medium may then be washed with water to remove aluminium salts, the organic
phase separated, dried for example over Na2SC"4, and evaporated.
The invention also relates to a method of the manufacture of a compound
of formula II
- X is CI, Br or I
- Y is H, F or an alkyl group having from 1 to 12 carbon atoms which is
optionally substituted by at least one halogen atom, an aralkyl group or an
aryl group ;
- R i is H or an organic residue
- R2 is H or an organic residue
which comprises the following steps
(a) producing a compound of formula (IV) : XYFCC(0)CH 2C(0)ORi ' (IV)
wherein R i , X and Y are as defined above, by addition of a fluorine
containing carboxylic acid chloride to ketene followed by esterification,
(b) adding an orthoformate of formula (III) : HC(OR3)3 (III) wherein R3 is
Ci-Cs-alkyl, C3 -C8 -cycloalkyl, C2-C -alkenyl, benzyl or phenyl, to the
compound of formula (IV) : XYFCC(0)CH 2C(0)ORi (IV) to produce an
and
(c) reacting said addition product with a hydrazine of formula (VI) :
R2 HNH2 (VI) wherein R2 is as defined above.
The definitions and preferences described above for the compounds used in
the process according to the invention equally apply to the method according to
the invention.
In a preferred embodiment of the method according to the invention, R3 in
the orthoformate of formula (III) is selected from the group consisting of C1-C4-
alkyl and benzyl and in particular from the group consisting of methyl, ethyl,
isopropyl and benzyl. R3 is especially ethyl.
It has been found, surprisingly, that the method according to the invention
makes it possible to prepare the compound of formula II with high
regioselectively and with a high yield.
In step (b) of the method of the manufacture of the compound of formula II
of the present invention, the addition reaction of the orthoformate of
formula (III) to the compound of formula (IV) can be carried out, for example,
analogously to the reaction described in WO 2008/053043.
Said addition reaction also forms an alcohol R3OH. The alcohol R3OH is
generally removed from the reaction equilibrium, for example in that it is
distilled off or bound chemically. In the latter, for example the reaction can be
carried out in the presence of an anhydride of a carboxylic acid, for example a
Ci-C4-alkanecarboxylic acid, such as acetic anhydride.
In the method according to the invention, the molar ratio of the
orthoformate of formula (III) to the compound of formula (IV) preferably is from
1.1 to 5, and particularly preferably from 1.2:2 to about 2 . Most preferably, the
molar ratio is about 2 .
In the method according to the invention, step (b) is generally carried out at
a temperature from 80°C to 180°C, preferably from 100°C to 150°C, more
preferably from 120°C to 140°C.
If desired, the compound of formula (V) is purified prior to being used in
step (c) of the method according to the invention. Examples of purification steps
which can be used to purify the compound of formula (V) include removal of
solvents, extraction, distillation, chromatography, or a combination of these
methods. It is preferred to subject the reaction mixture obtained in step (b) of the
method according to the invention to a distillation.
The method according to the invention advantageously avoids the use of
expensive starting materials, in particular 2,2-difluoroacetoacetic esters instead it
is possible to use the much less expensive halodifluoromethyl compounds, such
as 2-chloro-2,2-difluoroacetoacetic esters. For instance, 2,2-difluoroacetoacetic
esters are in general prepared by the Claissen reaction. For agrochemical
applications, said Claisen reaction often needs expensive bases and leads to
extensive waste formation. The preparation of the compounds of general
formula (IV) in step(a) by the ketene technology allows to avoid or minimize
waste formation and doesn't need an quite expensive base. According
to WO-A-2009/021987, the compounds of formula (IV) can be obtained, by
addition of fluorine containing carboxylic acid chlorides to ketene followed by
esterification. The used raw materials, such as difluorochloroacetyl chloride are
available in industrial scale and can be produced by environmentally friendly
technologies such as e.g. photochemical oxidation of 1,1-difluoro- 1,2,2-
trichloroethane with oxygen.
Some of the compounds of formula (IV) : XYFCC(0)CH 2C(0)ORi (IV),
produced in step (a) of the method of the present invention are commercially
available or can be prepared according to other known synthetic methods. For
instance, the compounds of formula (IV) can be prepared by Claisen
condensation of the corresponding fluorine containing carboxylate and acetate.
In the method according to the invention, the hydrazine of formula (VI)
can be used in step (c) in anhydrous or hydrate form. The hydrazine of
formula (VI) can be used for example as an anhydrous solution or an aqueous
solution. Preferably, said hydrazine is in the form of an anhydrous solution.
If desired, the hydrazine of formula (VI) can be dissolved in an organic
solvent, for example an organic solvent which comprises at least one halogen in
such as described above in the context process of the invention.
In one aspect of the method of the present invention, the hydrazine
compound (VI) in anhydrous form is added to a reaction solution comprising
compound (V) and an organic solvent which comprises at least one halogen.
In another aspect of the method of the present invention, the hydrazine
compound (VI) dissolved in an organic solvent, in particular the organic solvent
which comprises at least one halogen, is added to the reaction solution
comprising compound (V) and the organic solvent which comprises at least one
halogen.
In yet another aspect of the process of the present invention, the
compound (V) is added to the hydrazine compound (VI), preferably dissolved in
the organic solvent which comprises at least one halogen.
In an alternative and more preferred aspect of the process of the present
invention, the compound (V) present in the organic solvent which comprises at
least one halogen is added to the hydrazine compound (VI), preferably dissolved
in the organic solvent which comprises at least one halogen.
In the method according to the invention, the molar ratio of the hydrazine
of formula (VI) to the compound of formula (V) preferably is from 0.8 to 1.2,
and particularly preferably from 0.8 to 1.0 to about 1. Most preferably, the molar
ratio is about 1.
In the method according to the invention, the reaction in step (c) is
generally carried out in a solvent. The solvent to be used may, for example, be a
protic polar solvent, a hydrocarbon, an aliphatic hydrocarbon, an aprotic polar
solvent or an ionic liquid.
Examples of suitable protic polar solvents include aliphatic alcohols
having preferably 1 to 4 carbon atoms, such as methanol, ethanol, n-propanol,
isopropanol, n-butanol, isobutanol or tert-butanol.
Examples of suitable hydrocarbons include aromatic hydrocarbons,
aliphatic hydrocarbon or halogenated hydrocarbons.
Suitable aromatic hydrocarbons are selected, for example from benzene,
toluene, xylenes, cumene, chlorobenzene, nitrobenzene and tertbutylbenzene.
Suitable aliphatic hydrocarbons are selected for example from pentane,
hexane or octane.
Suitable halogenated hydrocarbons are selected for example from
hydrochlorocarbons such as dichloromethane, chloroform, carbon tetrachloride
or 1,2-dichloroethane, or hydrofluorocarbons such as 1,1,1,3,3-pentafluorobutane
(Solkane®365 mfc) or hydrochlorofluorocarbons, such as, 3,3-dichloro-l,l,l,2,2-
pentafluoropropane and/or l,3-dichloro-l,l,2,2,3-pentafluoropropane.
Examples of suitable aprotic polar solvents include ethers, amides, nitriles
such as acetonitrile or propionitrile or esters such as ethyl acetate, butyl acetate
or dimethyl carbonate.
Ethers may be cyclic or acyclic ethers, such as for example diethyl ether,
tert-butyl methyl ether (MTBE), tetrahydrofuran (THF) or dioxane. Amides may
be cyclic or acyclic, such as dimethylformamide, dimethylacetamide,
N-methylpyrrolidone or tetramethylurea.
These solvents may be used alone or in combination as a mixture.
The reaction in step (c) is preferably carried out in a halogenated
hydrocarbon, in particular in a hydrofluorocarbon and particularly preferably in
1,1,1,3,3-pentafluorobutane (Solkane®365 mfc). The use of a
hydrofluorocarbon, in particular 1,1,1,3,3-pentafluorobutane as solvent allows
for particularly efficient formation of the esters of l-substituted-3-fluoroalkylpyrazole-
4-carboxylic acid in very high regioselectivities.
In a preferred aspect of the method 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 is equal to or lower
than 1wt % by weight relative to the total weight of solvent, preferably equal to
or lower than 7000 ppm, more preferably equal to or lower than 5000 ppm, most
preferably equal to or lower than 2000 ppm. The solvent substantially free of
water generally contains at least lppm by weight of water, often at least 10 ppm
by weight of water relative to the total weight of solvent. Solvents which are
substantially free of water allow to maintain a high reaction rate and the
formation of phase separation and consequently, in general, no additional phase
transfer catalysts are required.
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.
If desired, the reaction in step (c) optionally may be carried out in the
presence of a base. If a base is used, it may be an inorganic base or an organic
base. When an inorganic base is used, it may be suitably selected from the group
consisting of alkali metal hydroxides such as sodium hydroxide, potassium
hydroxide, lithium hydroxide, cesium hydroxide, alkaline earth metal hydroxides
such as calcium hydroxide, barium hydroxide, magnesium hydroxide, strontium
hydroxide, and basic alkali metal salts such as sodium carbonate, sodium
hydrogencarbonate, potassium carbonate and potassium hydrogencarbonate.
Preferred bases are sodium hydroxide and potassium hydroxide. Most preferred
base is potassium hydroxide. When an organic base is used, it may be suitably
selected from the group consisting of nitrogen-containing heterocyclic
compounds such as pyridine, quinoline or picoline ; and tertiary bases such as
triethylamine, dimethylaniline, diethylaniline and 4-dimethylaminopyridine.
Among them, pyridine, triethylamine, dimethylaniline, diethylaniline and
4-dimethylaminopyridine are preferred. A single base can be used or a mixture
of several bases.
In the method according to the invention, step (c) is generally carried out at a
temperature from -20°C to 60°C, preferably from 0°C to 50°C, more preferably
from 10°C to 40°C. In a specific embodiment, an initial reaction temperature is
set and the reaction temperature is changed during the reaction. Typical initial
reaction temperatures range from -60 to 0°C, in particular from -60 to -20°C.
Good results were obtained with the temperature set from -30 to -20°C. If
appropriate, during the reaction the reaction mixture is warmed to a temperature
of from 0 to 60°C, in particular from 10 to 40°C.
It has been found that the compounds of formula (II) are stable to decomposition
but reactive towards hydrogenation.
In a most preferred aspect of the invention described herein, the compound
of formula (I) is an ester of l-methyl-3-difluoromethyl-pyrazole-4-carboxylic
acid, in particular the ethyl ester.
This compound can be obtained for example from the reduction of an ester
of l-methyl-3-chlorodifluoromethyl-pyrazole-4-carboxylic acid as compound of
formula (II), in particular the ethyl ester, with hydrogen using palladium on
carbon support as suitable catalyst.
In a preferred embodiment of this especially preferred process of the
present invention,
(a) the l-methyl-3-chlorodifluoromethyl-pyrazole-4-carboxylic acid as
compound of formula (II), in particular the ethyl ester, is obtained from the
reaction of an ester of 2-(ethoxymethylene)-4-chloro-4,4-difluoro-3-
oxobutanoic acid as compound of formula (V), in particular the ethyl ester,
with methylhydrazine as compound of formula (VI).
(b) said 2-(ethoxymethylene)-4-chloro-4,4-difluoro-3-oxobutanoic acid is
formed by the addition reaction of an orthoformate of formula (III), in
particular triethyl orthoformate, to an ester of 4-chloro-4,4-difluoro-3-
oxobutanoic acid as compound of formula (IV), in particular the ethyl ester.
The invention also concerns the use of the compound of formula (I) or
formula (II) in accordance with the invention as an intermediate in the
manufacture of an agrochemically or pharmaceutically active compound.
The invention also concerns a process for the manufacture of an
agrochemically or pharmaceutically active compound which comprises the use,
the process or the method according to the invention. Particularly, the compound
of formula (II) according to the invention can be (a) used as starting material in
the process according to the invention to produce compound of formula (I)
and (b) the compound of formula (I) is further reacted to manufacture an
agrochemically or pharmaceutically active compound. An example of further
reaction according to step (b) is illustrated in WO 2005/123690, the respective
content of which is incorporated by reference into the present patent application.
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 example is intended to further explain the invention without
limiting it.
Example 1 :
Preparation of ethyl- 4,4-difluoro-4-chloro 3-oxo-butanoic acid
In a three-neck round bottom flask, chlorodifluoroacetyl chloride (148.92g,
1 mol) was dissolved in methylene chloride (500 mL) and the solution was
cooled to -30°C. During 2 hours, ketene from a ketene generator (at a rate of
ca. 930 mmol/h) was passed through the solution of chlorodifluoroacetyl
chloride. The reaction mixture was warmed up to 0°C and kept for 1 hour
at 0°C. Ethanol (61.98 g, 1.94 mol) was added dropwise to the solution while
keeping the temperature below 5°C. The solution was stirred for another
0.5 hour. The reaction mixture was transferred to a 2-liter flask and concentrated
on a rotary evaporator under reduced pressure (30°C, 300 mBar). The residue
(282.78 g) was further distilled over a 60-cm Vigreux column under a pressure
of 30 mBar. Ethyl- 4,4-difluoro-4-chloro 3-oxo-butanoic acid was recovered at a
temperature of 58-65°C as a colorless liquid. The yield was 85 % of the
theoretical yield, and a purity of 98.0 % was obtained.
Example 2 : Preparation of ethyl l-methyl-3-chlorodifluoromethyl-pyrazole-4-
carboxylate (CDFMMP)
A solution of ethyl 4-chloro-4,4-difluoro-3-oxo-butanoate (19 g, 95 mmol),
triethyl orthoformate (28 g, 190 mmol) and acetic anhydride (29 g, 284 mmol)
were heated to 120 to 140°C with continuous removal of the low boilers, like
ethyl acetate produced. After 7 h the low volatility components are removed in
vacuum yield more or less quantitative, although during distillation of the
product variable yields are observed.
Crude ethyl 2-(ethoxymethylene)-4-chloro-4,4-difluoro-3-oxobutanoate
(95 mmol) dissolved in the solvent Solkane®365 mfc (200 mL)is reacted with
methylhydrazine (4.9 mL, 95 mmol) under ice cooling. GC shows a ratio
of 85 % CDFMMP to 15 % of the regio isomer. After 1 h at room temperature
the reaction mixture is washed with 2 N HC1 (100 mL) and water (100 mL).
After drying with sodium sulfate, filtration and concentration under reduced
pressure the desired product (14 g, 64 % over 2 steps) is isolated by column
chromatography .
Examples 3-20 : Reduction of CDFMMP to ethyl l-methyl-3-difluoromethylpyrazole-
4-carboxylate (DFMMP) by reduction in the presence of zinc and an
alcohol
The reduction of CDFMMP was carried out in an autoclave in the presence
of zinc and optional additive, during 3 hours at 70°C, except examples 15-20
which were carried out during 6 hours. The experimental data are summarized in
Table 1.
Table 1 :
The DFMMP yield was measured by GC analysis (peak %).
a Reaction conducted at room temperature
Finkelstein in DMF
MgF2 added after 2 hours and heated fro +4 hours
Examples 21-55 : Reduction of CDFMMP to ethyl l-methyl-3-difluoromethylpyrazole-
4-carboxylate (DFMMP) in the presence of supported Pd as
hydrogenation catalyst
The reduction of CDFMMP was carried out with hydrogen in an autoclave
in the presence of supported Pd catalyst and optional additives, at different
temperatures, under different H2 pressure and different reaction times. The
experimental data are summarized in Tables 2 and 3 .
As a more specific example, trial 53 was conducted as follows. 95 mg
of CDFMMP (0.42 mmol) were dissolved in about 2 mL of THF. To this
solution were added 64 mg of cesium fluoride (0.42 mmol), and 20 mg of Pd
10 % on carbon support. The mixture was stirred in a steel reator at 70°C
for 3 hours at 1 bar hydrogen pressure (measured by rt). The reaction medium
was cooled down, solids were filtered and washed with THF, and solvent was
evaporated yielding crude crystalline DFMMP. The DFMMP yield was
measured by GC analysis (peak %). The selectivity to DFMMP is given by the
following formula :
Selectivity (%) = DFMMP Yield (%) / [Me-MMP Yield (%) + CFH2-MMP]
Table 2 :
traces of full reduction of CF2C 1 group to CH3 group
Table 3 :
Examples 56-64 : Reduction of CDFMMP to ethyl l-methyl-3-difluoromethylpyrazole-
4-carboxylate (DFMMP) in the presence of Pd(OH)2/C as
hydrogenation catalyst
The reduction of CDFMMP was carried out with hydrogen in an autoclave
in the presence of Pd(OH)2 20 % on carbon (Pearlman's catalyst) and optional
additives, at different temperatures, under different H2 pressure and different
reaction times. The experimental data are summarized in Table 4 .
As a more specific example, trial 62 was conducted as follows. 95 mg
of CDFMMP (0.42 mmol) were dissolved in about 3 mL of THF. To this
solution were added 32 mg of cesium fluoride (0.21 mmol), 40 mg of flash silica
gel, 60 mg of potassium carbonate (0.43 mmol), and 20 mg of Pd(OH)2 20 % on
carbon support. The mixture was stirred in a steel reator at 110°C for 2 hours at
10 bar hydrogen pressure (measured by rt). The reaction medium was cooled
down, solids were filtered and washed with TFIF, and solvent was evaporated
yielding crude crystalline DFMMP. The DFMMP yield was measured by GC
analysis (peak %). The selectivity to DFMMP is given by the following
formula :
Selectivity (%) = DFMMP Yield (%) / [Me-MMP Yield (%) + CFH2-MMP]
Table 4 :
* 365 = 1,1,1,3,3-pentafluorobutane (Solkane®365 mfc)
Examples 65-67 : Reduction of CDFMMP to ethyl l-methyl-3-difluoromethylpyrazole-
4-carboxylate (DFMMP) in the presence of Raney Nickel as
hydrogenation catalyst
The reduction of CDFMMP was carried out with hydrogen in an autoclave
in the presence of Raney Nickel catalyst and optional additives, at different
temperatures, under different H2 pressure and different reaction times. The
experimental data are summarized in Table 5 .
As a more specific example, trial 67 was conducted as follows. 28 g
of CDFMMP (126 mmol) were dissolved in about 200 mL water in a steel
reactor. To this solution were added 1.05 g of wet Raney Nickel and 15 ml of
28 % aqueous ammonia solution. The mixture was stirred (700 rpm) at 70°C
for 24 hours at 11 bar hydrogen constant pressure. The reaction medium was
cooled down, extracted 2 times with solvent Solkane®365 mfc, organic phase
was dried over Na2S0 4, and was evaporated to yield DFMMP. The DFMMP
yield was measured by GC analysis (peak %). The selectivity to DFMMP is
given by the following formula :
Selectivity (%) = DFMMP Yield (%) / [Me-MMP Yield (%) + CFH2-MMP]
Table 5 :
Examples 68-70 : Reduction of CDFMMP to ethyl l-methyl-3-difluoromethylpyrazole-
4-carboxylate (DFMMP) in the presence of RJ1/AI2O3 as hydrogenation
catalyst
The reduction of CDFMMP was carried out with hydrogen in an autoclave
in the presence of Rh/Al 20 3catalyst and optional additives, at different
temperatures, under different H2 pressure and different reaction times. The
experimental data are summarized in Table 6 .
As a more specific example, trial 68 was conducted as follows. 95 mg of
CDFMMP (0.42 mmol) were dissolved in about 2 mL of EtOH. To this solution
were added 64 mg of cesium fluoride (0.42 mmol), and 90 mg of Rh 5 % on
alumina support. The mixture was stirred in a steel reator at 80°C for 20 hours
at 1 bar hydrogen pressure (measured by rt). The DFMMP yield was measured
by GC analysis (peak %). The selectivity to DFMMP is given by the following
formula :
Selectivity (%) = DFMMP Yield (%) / [Me-MMP Yield (%) + CFH2-MMP]
Table 6 :

C L A I M S
1. A process for the manufacture of an ester of a 1-substituted-3-
fluoroalkyl-pyrazole-4-carboxylic acid of formula (I)
wherein
- Y is H, F or an alkyl group having from 1 to 12 carbon atoms which is
optionally substituted by at least one halogen atom, an aralkyl group or
aryl group,
- Ri is H or an organic residue,
- R2 is H or an organic residue,
which comprises submitting a compound of formula (II)
wherein Y is as defined above
- X is CI, Br or I,
- Ri is H or an organic residue,
- R2 is H or an organic residue,
to a reduction reaction.
2 . The process according to claim 1, wherein Ri is methyl, ethyl,
n-propyl or isopropyl, preferably ethyl.
3 . The process according to anyone of claims 1 to 2, wherein R2 is
methyl.
4 . The process according to anyone of claims 1 to 3, wherein X is CI and
Y is F.
5 . The process according to anyone of claims 1 to 4, wherein the
reduction is carried out with hydrogen in the presence of a hydrogenation
catalyst, preferably chosen from the metals from Group VIII of the Periodic
Table of the Elements, more preferably comprising at least one metal chosen
from nickel, palladium, platinum and rhodium, most preferably Raney nickel and
palladium.
6 . The process according to claim 5 wherein the catalyst is a supported
catalyst, preferably with a support selected from alumina, silica and carbon,
especially supported palladium, more especially palladium on carbon support
(Pd/C) or palladium hydroxide on carbon support (Pd(OH) 2/C).
7 . The process according to any one of claims 1 to 6, wherein the
temperature of the reaction is from -10°C to 150°C, in particular 20°C to 120°C,
more particularly 40°C to 120°C.
8 . The process according to any one of claims 1 to 7, wherein the
pressure of the reaction is from 1 bar absolute to 30 bar absolute and wherein the
molar ratio of hydrogen to a compound of formula (II) is from 1 to 1000,
especially 1 to 100.
9 . The process according to any one of claims 1 to 8, wherein the
reduction reaction is conducted in the presence of at least one additive, especially
at least one additive selected from organic bases, inorganic bases or a salts, more
particularly in the presence of at least one of K2C0 3, H4CI, H4F, CsF and
Borax, preferably at least CsF.
10. A method for the manufacture of a compound of formula II
(II)
wherein
- X is CI, Br or I,
- Y is H, F or an alkyl group having from 1 to 12 carbon atoms which is
optionally substituted by at least one halogen atom, an aralkyl group or an
aryl group,
- Ri is H or an organic residue,
- R2 is H or an organic residue,
which comprises which comprises the following steps
(a) producing a compound of formula (IV) : XYFCC(0)CH 2C(0)ORi ' (IV)
wherein Ri , X and Y are as defined above , by addition of a fluorine
containing carboxylic acid chloride to ketene followed by esterification
(b) adding an orthoformate of formula (III) : HC(OR3)3 (III) wherein R3 is
Ci-Cs-alkyl, C3-C8 -cycloalkyl, C2-C -alkenyl, benzyl or phenyl, to the
compound of formula (IV) : XYFCC(0)CH 2C(0)ORi (IV) to produce an
addition product of formula (V) :
wherein Ri , R3, X and Y are as defined above
and
(c) reacting said addition product with a hydrazine of formula (VI) :
R2 HNH2 (VI) wherein R2 is as defined above.
11. The method according to claim 10, wherein X is CI and Y is F.
12. The method according to the claims 10 and 11, wherein the reaction in
step (b) is carried out in a hydrofluorocarbon solvent, preferably
1,1,1,3,3 -pentafluorobutane .
13. The process according to anyone of claims 1 to 9 wherein the
compound of formula II is obtained according to anyone of claims 10 to 12.
14. Use of the compound of formula (I), obtained according to claims 1
to 13, as an intermediate in the manufacture of an agrochemically or
pharmaceutically active compound.
15. A process for the manufacture of an agrochemically or
pharmaceutically active compound which comprises the use according to
claim 14.