PROCEDURE FOR THE SYNTHESIS OF
N-BENZYL-N-CYCLOPROPYL-1 H-PYRAZOLE-4-CARBOXAMIDE DERIVATIVES
The present invention concerns the oxidative coupling of secondary benzylic amines with
pyrazol carbaldehydes for the synthesis of pyrazole carboxamide derivatives. The synthesis of
these compounds was described by WO 2010/130767 as a synthesis over two or more steps,
starting from a pyrazol carbaldehyde via oxidation to the corresponding acid halogenide and
its reaction with a benzylamine to the desired target compound in the final step.
A synthesis of fluorinated pyrazolcarbaldehydes was described in patent WO 201 1/061205.
Secondary benzylic amines can be prepared as described in patent WO 2012/059585.
The direct oxidative coupling of aromatic aldehydes and secondary benzylic amines to the
corresponding amide is described to some extent in literature. The group of Chen reported the
oxidative amidation of various aldehydes with primary and secondary amine hydrochlorides
in presence of base, an iron or copper catalyst and t rt-Butylhydroperoxide as oxidant (J. Org.
Chem. 2012, 77, 8007-8015; Adv. Synth. Catal. 2012, 354, 1407 - 1412). Pevarello et al.
reported one example of oxidative coupling of an imidazothiadiazole carbaldehyde with Nmethylbenzylamine
in presence of t r t-butylhydroperoxide in 29% yield (WO 2009/040552).
However, the oxidative coupling of pyrazolcarbaldehydes, let alone fluorinated
pyrazolcarbaldehydes with secondary benzylic amines is not known in literature. In addition,
most of the literature procedures for oxidative coupling of aldehyde with amines describe the
use of excess aldehyde or amine, which decreases the economic efficiency of the reaction
considerably.
Proceeding from this prior art it is the object of the present invention to provide an efficient
method for the synthesis of pyrazole-4-carboxamides from a pyrazol carbaldehyde and
secondary benzylic amines in only one step and without employing expensive transition metal
catalysts or excess amounts of amine respectively aldehyde.
The present invention relates to a process for preparation of pyrazole carboxamides of the
formula (I)
wherein R is selected from the list of 2-isopropylphenyl, 2-cyclopropylphenyl, 2-tertbutylphenyl,
5-chloro-2-ethylphenyl, 5-chloro-2-isopropylphenyl, 2-ethyl-5-fluorophenyl, 5-
fluoro-2-isopropylphenyl, 2-cyclopropyl-5-fluorophenyl, 2-cyclopentyl-5-fluorophenyl, 2-
fluoro-6-isopropylphenyl, 2-ethyl-5-methylphenyl, 2-isopropyl-5-methylphenyl, 2-
cyclopropyl-5-methylphenyl, 2-tert-butyl-5-methylphenyl, 5-chloro-2-
(trifluoromethyl)phenyl, 5-methyl-2-(trifluoromethyl)phenyl, 2-chloro-6-
(trifluoromethyl)phenyl, 3-chloro-2-fluoro-6-(trifluoromethyl)phenyl and 2-ethyl-4,5-
dimethylphenyl,
by reaction of 3-(difluoromethyl)-5-fluoro-l -methyl- lH-pyrazole-4-carbaldehyde of the
formula (II)
with an amine of the general formula (Ilia) or its salt of the general formula (Illb)
(Ilia) (Illb)
wherein HX is selected from the list of HF, HCl, HBr, HJ; H2SO4, HBF4, CH3SO3H,
CF3SO3H, CF3CO2H and R is as defined above,
in presence of an oxidant and with a catalyst.
In a particular embodiment of the invention, the amine derivative or its hydrochloride salt is
of formula III-l
The process according to the invention is preferably used to prepare a compound of formula (I)
selected from the group consisting of:
N-cyclopropyl-3-(difluoromethyl)-5-fluoro-N-(2-isopropylbenzyl)-l -methyl- lH-pyrazole-4-
carboxamide ,
N-cyclopropyl-N-(2-cyclopropylbenzyl)-3-(difluoromethyl)-5 -fluoro- 1-methyl- lH-pyrazole-
4-carboxamide ,
N-(2-tert-butylbenzyl)-N-cyclopropyl-3 -(difluoromethyl)-5 -fluoro- 1-methyl- 1H-pyrazole-4-
carboxamide ,
N-(5-chloro-2-ethylbenzyl)-N-cyclopropyl-3 -(difluoromethyl)-5 -fluoro- 1-methyl- 1Hpyrazole-
4-carboxamide ,
N-(5-chloro-2-isopropylbenzyl)-N-cyclopropyl-3-(difluoromethyl)-5 -fluoro- 1-methyl- 1Hpyrazole-
4-carboxamide ,
N-cyclopropy 1-3-(difluoromethy l)-N-(2-ethyl-5 -fluorobenzyl)-5 -fluoro- 1-methyl- 1Hpyrazole-
4-carboxamide ,
N-cyclopropyl-3 -(difluoromethyl)-5 -fluoro-N-(5 -fluoro-2-isopropylbenzyl)- 1-methyl- 1Hpyrazole-
4-carboxamide ,
N-cyclopropyl-N-(2-cyclopropyl-5-fluorobenzyl)-3 -(difluoromethyl)-5 -fluoro- 1-methyl- 1Hpyrazole-
4-carboxamide ,
N-(2-cyclopentyl-5 -fluorobenzyl)-N-cyclopropyl-3 -(difluoromethyl)-5 -fluoro- 1-methyl- 1Hpyrazole-
4-carboxamide ,
N-cyclopropyl-3 -(difluoromethyl)-5 -fluoro-N-(2-fluoro-6-isopropylbenzyl)- 1-methyl- 1Hpyrazole-
4-carboxamide ,
N-cyclopropy1-3-(difluoromethyl)-N-(2-ethyl-5-methylbenzyl)-5-fluoro- 1-methyl- 1Hpyrazole-
4-carboxamide ,
N-cyclopropyl-3 -(difluoromethyl)-5-fluoro-N-(2-isopropyl-5-methylbenzyl)- 1-methyl- 1Hpyrazole-
4-carboxamide ,
N-cyclopropyl-N-(2-cyclopropyl-5-methylbenzyl)-3 -(difluoromethyl)-5-fluoro-1-methyl-1Hpyrazole-
4-carboxamide ,
N-(2-tert-butyl-5-methylbenzyl)-N-cyclopropyl-3 -(difluoromethyl)-5-fluoro- 1-methyl- 1Hpyrazole-
4-carboxamide ,
N-[5-chloro-2-(trifluoromethyl)benzyl]-N-cyclopropyl-3-(difluoromethyl)-5-fluoro-l -methyl
lH-pyrazole-4-carboxamide (compound A15),
N-cyclopropy1-3-(difluoromethyl)-5 -fluoro- 1-methyl-N-[5-methyl-2-
(trifluoromethyl)benzyl]-lH-pyrazole-4-carboxamide (compound A16),
N-[2-chloro-6-(trifiuoromethyl)benzyl]-N-cyclopropyl-3-(difiuoromethyl)-5-fiuoro-l -methyl
lH-pyrazole-4-carboxamide,
N-[3-chloro-2-fluoro-6-(trifiuoromethyl)benzyl] -N-cyclopropyl-3-(difiuoromethyl)-5-fluoro-
1-methyl-1H-pyrazole-4-carboxamide .
N-cyclopropy1-3-(difluoromethyl)-N-(2-ethyl-4,5-dimethylbenzyl)-5-fluoro-1-methyl- 1Hpyrazole-
4-carboxamide ,
and N-cyclopropyl-3 -(difiuoromethyl)-5-fiuoro-N-(2-isopropylbenzyl)-l -methyl-1Hpyrazole-
4-carbothio-amide .
Process description
The oxidative amidation step is performed in the presence of an oxidant, a catalyst and
optionally a base.
The ratio between amine III and aldehyde II can vary from 1.5:1 to 1:0.5, preferably from
1.2:1 to 1:0.5, most prefereably from 1.2:1 to 1:1.
The oxidant is selected from sodium hypochlorite, cumenehydroperoxide, tertbutylhydroperoxide,
hydrogenperoxide, sulfurylchloride, N-bromosucinimide, Nchlorosuccinimide,
meta-chloroperbenzoic acid, bromine; preferred are sulfurylchloride, tertbutylhydroperoxide
and cumenehydroperoxide, most preferred are t r t-butylhydroperoxide
and cumenehydroperoxide.
The amount of the oxidant can vary from 0.5-5 equivalents; preferably from 1-2.5
equivalents, more preferably from 1.5-2.5
If amine salt Illb is employed in the reaction, then a base is used for this process and is either
an organic or inorganic base. A single compound or a mixture is selected from Na2C0 3,
NaOH, K2CC"3, CaCC"3, CaO, Ca(OH) 2 or an organic base such as Et3N; preferred are
Na2C0 3; K2C0 3, CaC0 3, especially preferred is CaC0 3.
The catalyst is selected from CuS04*5H20 , FeS04*7H 20 , CoS04*7H20 , NiS0 4, preferred is
CuS04*5H 20 , FeS0 4*7H20 , especially preferred is FeS0 4*7H20 .
The reaction is performed in the presence of a solvent, which can be selected from toluene,
methanol, valeronitrile, acetonitrile, N N-dimethylformamide, water, tetrachloromethane,
chloroform, chlorobenzene, preferably valeronitrile and acetonitrile, more preferably
acetonitrile.
The reaction time of the process according to the invention is generally not of critical
importance and can depend on the reaction volume; preferably it is within the range of 3 to
12h.
The temperature of the process according to the invention is ranging from 0°C to 150°C;
preferably from 20 °C to 120 °C, more preferably from 60 °C to 90 °C.
Examples
Example 1:N-(5-chloro-2-isopropvlbenzvl)-N-cvclopropvl-3-(difluoromethvl)-5-fluoro-lmethyl-
1H-pyrazole-4-carboxamide
To a mixture of FeS04*7H 20 (0.55 mmol, 0.15 g), CaCOs (5.63 mmol, 0.563 g) and N-(5-
chloro-2-isopropylbenzyl)cyclopropylamine hydrochloride (2.8 mmol, 0.725 g) in acetonitrile
(2 g) was added 3-(difluoromethyl)-5-fluoro-l-methyl-l H-pyrazole-4-carbaldehyde (2.8
mmol, 0.5 g). The suspension was heated to 60 °C and a solution of t-Butylhydroperoxide
(7.7 mmol, 0.69 g) in acetonitrile (2g) was added over 10 hours. The resulting mixture was
treated with 1M hydrochloric acid, extracted with dichloromethane, the organic layer washed
with sodiumbisulfit solution and concentrated in vacuo to obtain the the crude product (60%
purity by quantitative LC, 1.02 g, 57%> theoretical yield).
¾ NMR (DMSO-d6, 600 MHz, 25 °C): d = m7.38 - 7.37 (m, 1H), 7.34 -7.32 (m, 1H), 7.20
(m, 1H), 6.99 (t, 1H, CF2H, JH-F = 54 Hz), 4.69 (s, 2H), 3.80 (s, 3H, N-CH3), 3.18 - 3.10 (br m,
1H), 2.63 - 2.48 (br m, 1H), 1.18 (d, 6H, J = 6.6 Hz), 0.67 - 0.63 (m, 4H) ppm.
Example 2 : A further procedure for synthesis of N-(5-chloro-2-isopropylbenzyl)-Ncyclopropyl-
3 -(difluoromethyl)-5 -fluoro- 1-methyl- 1H-pyrazole-4-carboxamide
To a mixture of FeS04*7H 20 (0.26 mmol, 0.073 g), CaC0 3 (0.53 mmol, 0.053 g) and N-(5-
chloro-2-isopropylbenzyl)cyclopropylamine hydrochloride (0.94 mmol, 0.167 g) in
acetonitrile (0.9 g) was added 3-(difluoromethyl)-5-fluoro-l-methyl-l H-pyrazole-4-
carbaldehyde (0.56 mmol, 0.1 g). The suspension was heated to 60 °C and aqueous NaOCl
solution (13 wt-%; 0.58 mmol, 0.331 g) was added. The resulting mixture was stirred until
LCMS of the crude reaction indicated the formation of the target product.
Example 3:A further procedure for synthesis of N-(5-chloro-2-isopropylbenzyl)-Ncyclopropyl-
3 -(difluoromethyl)-5 -fluoro- 1-methyl- 1H-pyrazole-4-carboxamide
The procedure was followed as described in Example 2 but with aqueous H2O2 solution (30
wt-%) instead of NaOCl as the oxidant.
Example 4 : A further procedure for synthesis of N-(5-chloro-2-isopropylbenzyl)-Ncyclopropyl-
3 -(difluoromethyl)-5 -fluoro- 1-methyl- lH-pyrazole-4-carboxamide
The procedure was followed as described in Example 1 but with N,N -Dimethylformamide as
solvent instead of acetonitrile.
Example :A further procedure for synthesis of N-(5-chloro-2-isopropylbenzyl)-Ncyclopropyl-
3 -(difluoromethyl)-5 -fluoro- 1-methyl- lH-pyrazole-4-carboxamide
The procedure was followed as described in Example 1 but with methanol as solvent instead
of acetonitrile.
Example 6 : A further procedure for synthesis of N-(5-chloro-2-isopropylbenzyl)-Ncyclopropyl-
3 -(difluoromethyl)-5 -fluoro- 1-methyl- lH-pyrazole-4-carboxamide
The procedure was followed as described in Example 1 but with toluene as solvent instead of
acetonitrile.
Example 7 : A further procedure for synthesis of N-(5-chloro-2-isopropylbenzyl)-Ncyclopropyl-
3 -(difluoromethyl)-5 -fluoro- 1-methyl- lH-pyrazole-4-carboxamide
To a mixture of FeS04*7H 20 (0.26 mmol, 0.074 g), CaCOs (10.7 mmol, 1.072 g) and N-(5-
chloro-2-isopropylbenzyl)cyclopropylamine hydrochloride (6.0 mmol, 1.564 g) in acetonitrile
(4 g) was added 3-(difluoromethyl)-5-fluoro-l-methyl-l H-pyrazole-4-carbaldehyde (5.6
mmol, 1 g). The suspension was heated to 60 °C and a solution of cumenehydroperoxide (8.7
mmol, 1.325 g) in acetonitrile (3.5 g) was added over 5 hours. The resulting mixture was
treated with with sodiumbisulfit and extracted with dichloromethane. The resulting organic
layer was concentrated in vacuo to obtain the crude product (24% purity by quantitative LC,
2.3 g, 26%).
Example 8 : A further procedure for synthesis of N-(5-chloro-2-isopropylbenzyl)-Ncyclopropyl-
3 -(difluoromethyl)-5 -fluoro- 1-methyl- 1H-pyrazole-4-carboxamide
To a mixture of FeS04*7H 20 (0.025 mmol, 0.007 g), CaCOs (0.053 mmol, 0.053 g) and N-
(5-chloro-2-isopropylbenzyl)cyclopropylamine hydrochloride (0.94 mmol, 0.167 g) in
acetonitrile (0.9 g) was added 3-(difluoromethyl)-5-fluoro-l-methyl-l H-pyrazole-4-
carbaldehyde (0.56 mmol, 0.1 g). The suspension was heated to 60 °C and a solution of t-
Butylhydroperoxide (0.57 mmol, 0.074 g) was added. The resulting mixture was stirred until
LCMS of the crude reaction indicated the formation of the target product.
Patent Claims
1. Process for the synthesis of pyrazole carboxamide of the formula (I)
wherein R is selected from the list of 2-isopropylphenyl, 2-cyclopropylphenyl, 2-tertbutylphenyl,
5-chloro-2-ethylphenyl, 5-chloro-2-isopropylphenyl, 2-ethyl-5-
fluorophenyl, 5-fluoro-2-isopropylphenyl, 2-cyclopropyl-5-fluorophenyl, 2-
cyclopentyl-5-fluorophenyl, 2-fluoro-6-isopropylphenyl, 2-ethyl-5-methylphenyl, 2-
isopropyl-5-methylphenyl, 2-cyclopropyl-5-methylphenyl, 2-tert-butyl-5-
methylphenyl, 5-chloro-2-(trifluoromethyl)phenyl, 5-methyl-2-
(trifluoromethyl)phenyl, 2-chloro-6-(trifluoromethyl)phenyl, 3-chloro-2-fluoro-6-
(trifluoromethyl)phenyl and 2-ethyl-4,5-dimethylphenyl,
by reaction of 3-(difluoromethyl)-5-fluoro-l-methyl-lH-pyrazole-4-carbaldehyde of
the general formula (II)
with an amine of the general formula (Ilia) or its salt of the general formula (Illb)
(Ilia) (Illb)
wherein HX is selected from the list of HF, HCl, HBr, HJ; H2SO4, HBF4, CH3SO3H,
CF3SO3H, CF3CO2H and R is as defined above,
in presence of an oxidant and with a catalyst.
2. Process according to claim 1, wherein the amine derivative or its hydrochloride salt
are of formula III- 1
3. Process according to any one of claims 1 to 2 for preparation of a carboxamide
derivative selected from the group consisting of :
N-cyclopropyl-3-(difluoromethyl)-5-fluoro-N-(2-isopropylbenzyl)-l-methyl-lHpyrazole-
4-carboxamide (compound Al),
N-cyclopropyl-N-(2-cyclopropylbenzyl)-3-(difluoromethyl)-5-fluoro-l-methyl-lHpyrazole-
4-carboxamide (compound A2),
N-(2-tert-butylbenzyl)-N-cyclopropyl-3-(difluoromethyl)-5-fluoro-l-methyl-lHpyrazole-
4-carboxamide (compound A3),
N-(5-chloro-2-ethylbenzyl)-N-cyclopropyl-3-(difluoromethyl)-5-fluoro-l-methyllH-
pyrazole-4-carboxamide (compound A4),
N-(5-chloro-2-isopropylbenzyl)-N-cyclopropyl-3-(difluoromethyl)-5-fluoro-lmethyl-
lH-pyrazole-4-carboxamide (compound A5),
N-cyclopropyl-3-(difluoromethyl)-N-(2-ethyl-5-fluorobenzyl)-5-fluoro-l-methyllH-
pyrazole-4-carboxamide (compound A6),
N-cyclopropyl-3-(difluoromethyl)-5-fluoro-N-(5-fluoro-2-isopropylbenzyl)-lmethyl-
lH-pyrazole-4-carboxamide (compound A7),
N-cyclopropyl-N-(2-cyclopropyl-5-fluorobenzyl)-3-(difluoromethyl)-5-fluoro-lmethyl-
lH-pyrazole-4-carboxamide (compound A8),
N-(2-cyclopentyl-5-fluorobenzyl)-N-cyclopropyl-3-(difluoromethyl)-5-fluoro- 1-
methyl- lH-pyrazole-4-carboxamide (compound A9),
N-cyclopropyl-3-(difluoromethyl)-5-fluoro-N-(2-fluoro-6-isopropylbenzyl)-lmethyl-
lH-pyrazole-4-carboxamide (compound A10),
N-cyclopropyl-3-(difluoromethyl)-N-(2-ethyl-5-methylbenzyl)-5-fluoro-l-methyllH-
pyrazole-4-carboxamide (compound All),
N-cyclopropyl-3-(difluoromethyl)-5-fluoro-N-(2-isopropyl-5-methylbenzyl)-lmethyl-
lH-pyrazole-4-carboxamide (compound A12),
N-cyclopropyl-N-(2-cyclopropyl-5-methylbenzyl)-3-(difluoromethyl)-5-fluoro-lmethyl-
lH-pyrazole-4-carboxamide (compound A13),
N-(2-tert-butyl-5-methylbenzyl)-N-cyclopropyl-3-(difluoromethyl)-5-fluoro-lmethyl-
lH-pyrazole-4-carboxamide (compound A14),
N-[5-chloro-2-(trifluoromethyl)benzyl]-N-cyclopropyl-3-(difluoromethyl)-5-fluoro-
1-methyl- lH-pyrazole-4-carboxamide (compound A15),
N-cyclopropyl-3-(difluoromethyl)-5-fluoro-l-methyl-N-[5-methyl-2-
(trifluoromethyl)benzyl]- lH-pyrazole-4-carboxamide (compound A16),
N-[2-chloro-6-(trifluoromethyl)benzyl]-N-cyclopropyl-3-(difluoromethyl)-5-fluoro-
1-methyl- lH-pyrazole-4-carboxamide (compound A17),
N-[3-chloro-2-fluoro-6-(trifluoromethyl)benzyl]-N-cyclopropyl-3-(difluoromethyl)-
5-fluoro-l-methyl-lH-pyrazole-4-carboxamide (compound A18).
N-cyclopropyl-3-(difluoromethyl)-N-(2-ethyl-4,5-dimethylbenzyl)-5-fluoro-lmethyl-
lH-pyrazole-4-carboxamide (compound A19),
and N-cyclopropyl-3-(difluoromethyl)-5-fluoro-N-(2-isopropylbenzyl)- 1-methyl- 1Hpyrazole-
4-carbothio-amide (compound A20).
4. Process according to any one of claims 1 to 3, wherein the oxidative step is performed
in presence of a base.
5. Process according to claim 4 wherein the base is selected from the list consisting of
Na2C0 3, NaOH, K2C0 3, CaC0 3, CaO, Ca(OH)2,Et3N or mixture thereof.
6. Process according to claim 4 or 5 wherein the base is CaCC
7. Process according to any one of claims 1 to 6, wherein the catalyst is selected from
the list consisting of CuS0 4*5H20 , FeS0 4*7H20 , CoS0 4*7H20 , NiSCk
8. Process according to claim 7, wherein the catalyst is FeS0 4*7H20
9. Process according to any one of claims 1 to 8, wherein the oxidant is selected from
the list of sodium hypochlorite, cumenehydroperoxide, ie/t-butylhydroperoxide,
hydrogenperoxide, sulfurylchloride, N-bromosucinimide, N-chlorosuccinimide, metachloroperbenzoic
acid, bromine.
10. Process according to claim 9 wherein the oxidant is selected from
cumenehydroperoxide or iert-butylhydroperoxide.
11. Process according to any one of claims 1 to 10, wherein the reaction is performed in
presence of a solvent selected from toluene, methanol, valeronitrile, acetonitrile,
N,N -dimethylformamide, water, tetrachloromethane, chloroform, or chlorobenzene.
12. Process according to claim 1 1 wherein the solvent is acetonitrile.