Note: Descriptions are shown in the official language in which they were submitted.
659 ~0~045S
1 The ~resent invention relates to a process for the
manufacture o~ 3,5-disubstituted pyrazoles. More particu-
larly, it relates to (a) the reaction of a methyl ketone,
such as acetophenone or an appropriate derivative thereof,
with an appropriate aldehyde, such as benzaldehyde, in the
presence of base to form a 1,3-disubstituted a,~-unsaturated
ketone, such as chalcone or a substituted chalcone, (b) the
acidification of said a,~-unsaturated ketone, followed by
treatment of the acidified reaction mixture with hydrazine to
10 form a disubstituted pyrazoline, and (c) the catalytic de- I
hydrogenation of said pyrazoline to obtain the desired 3,5- .
-disubstituted pyrazole.
In general, the overall reaction can be illustrated
graphically as follows: -
O
(I) RlCOCH3 ~ R2CHO ba~e ~ R2CH-CHCRl --
a methyl ketone a 1,3-di8ub-(1) mlneral
+ an aldehyde stltuted ~,~-acld, then
un8aturated
ketone (2) HZ~NH2
H20 ,,
H H
'tH2 + Rl--~ R2 <catalyqt R~
N N-H (dehydro- N----h-H
3,5-di8ubstituted a disub~tituted
pyrazole pyrazollne
wherein Rl is -~; R2 i8 ~ ; and Y, Y', Z and
Z Z'
Z' each independently represent members selected from the
group consisting of hydrogen, halogen, methylthio, methyl-
sulfonyl, cyano, carboxyl, carboalkoxy C1-C4, hydroxy, alkyl
C1-C4, haloalkyl Cl-C4 containing 1 to 4 halogen atoms, and
alkoxy Cl-C4-
- 1 -
45S
The term "halogen", as herein used, is intended to
mean fluorine, chlorine, iodine or bromine; ho~ever, fluorine,
chlorine and bromine are preferred.
The terms "alkyl" and "alkoxy" are intended to mean
~traight chain and branched chain alkyl and alkoxy, including
~traight and branched haloalkyl, and ~traight and branched
carboalkoxy.
In accordance with the process of this invention,
approximately equimolar amounts of the ketone, RlCOCH3, and
the aldehyde, R2CH0, are reacted in the presence of a base
and a Cl-C4 alcoholic solvent at a temperature range between
1~C. and 70C., acidifying said reaction mixture to a pH of
at least 7, treating the so-acidified reaction mixture with
from about 1.O to 2.0 mole equivalents of hydrazlne, adding
to ~aid reaction mixture a dehydrogenation catalyst heating
said mixture to refluxing temperatures, and recovering the
de~ired 3,5-di~ubstituted pyrazole in good yield and purity.
Exemplary bases include, for instance, alkali metal
Cl-C4alkoxides, ~uch as sodium or potassium methoxide, eth-
oxide, propoxide, butoxide, t-butoxide, and eguivalent~ there-
of, or aqueou~ sodium hydroxide or potas~ium hydroxide.
Aqueoue sodium hydroxide is, however, generally preferred.
The aforementioned ketone-aldehyde mixture i ~tir-
red, usually for several hours, and then acidified to a pH
of 7 or below, preferably to between 5 and 7, utilizing a
mineral acid such as hydrochloric acid, sulfuric acid or phos-
phoric acid. In practice, it will usually be found that the
mole ratio of acid required for pH adjustment will approximate
the mole ratio of base employed in the previous reaction.
Sub~equent to acidification, the reaction mixture
~ - 2 -
``"":~
1()~0~55
is treated with at least one mole equivalent, ox more, of hy-
drazine. The hydrazine employed may be anhydrous or in aque-
ous solution, and should be introduced into the reaction mix-
ture in ~uch manner as to maintain the temperature thereof
below 70C. and, preferably, between 20C. and 50C. Since
~ Z5
30 ~ ~
- 2a -
,~
. - - .- . ~ .. .. .- .. . . .. . . .
1060455
] ~:h~ ~caction is exothermic, coolin~ is ~3enerally required to
maintain the latter temperatures. Further, the reactio~
preferably carried out in an inert atmosphere in order to
exclude air from the reaction mixture and, .hus prevent any
oxidation of the intermediate pyrazoline. This can be ach-
ieved by conducting said reaction under a blanket of an inert
gas, sllch as nitrogen, helium, argon or carbon dioxide. In
~eneral, the hydrazine addition period should be relatively
rapid, since prolonged additions result in lower product
yield. It is a ~ood practice to complete the hydrazine addi-
tion within about sixty minutes, or less, both in a batch or
continuous operation.
Following the hydrazine addition, the reaction mix-
ture is heated to reflux, and subjected to catalytic dehydro-
genation. This catalytic dehydrogenation reaction is prefer-
ably carried out in an inert atmosphere, as for example, un-
der a blanket of nitrogen, argon, helium or carbon dioxide.
However, the provision for an inert atmosphere is not abso-
lutely essential, although it does improve product yield.
The dehydrogenation can be carried out in a variety of [se-
lected] solvents or solvent mixtures by first distilling off
the alcohol and replacing it with the selected solvent. The
~ .
prefer~ed solvent is xylene per se or any available mixtures
of ortho, meta and para xylenes. However, other solvents are
~suitable. Exemplary solvents include, for instance, (a) ben-
zene, toluene, heavy aromatic solvents such as PANASOL~ AN-2,
AN-3 or AN-5, ESSO HAN~, SOCAL 44 L, and the like, which have
~ ,: :
; a mixed aniline point above 30F. but not exceeding 95F.,
an aromatic content between 60~ and 100%, and a specific
.
~ravity at 60/60~F. between 0.88 and 1.5; (b) cyclic ~thers
such as dioxane and tetrahydrofuran (T~IF); (c) polar aprotic
solvents such as acetonitrile and dimethylformamide (DM~);
or (d) chlorinated hydrocarbons, such as chloroform, per-
- 3 -
,
1()~0~55
chloroethylene or ethylene dichloride. After the alcohol sol-
vent i8 removed by distillation, and the selected solvent from
the above-mentioned group of solvents, preferably xylenes or
mixed xylenes, is added, the reaction mixture i8 cooled to
between 40~C. and 70C., and washed with water to remove
alkali metal salts, alcohol and any unreacted hydrazine. The
cataly~t i8 selected from the group consisting of platinum,
palladium, platinum or alumina, platinum on barium sulfate,
palladium on alumina, palladium on barium qulfate, palladium
on carbon, platimun on carbon and pre-reduced copper chromite
i8 added to the reaction mixture while maintaining an inert
ga~ flow over the reaction mixture. In practice, the catalyst
should be introduced to the charge (at a temperature between
40C. to 60C.) as a water wet solid or admixed in a solvent
a~ a ~lurry.
m e overall reaction mixture is then brought to
reflux and residual water removed by azeotropic di~tillation.
Refluxing is continued while maintaining an inert gas flow
to insure both complete removal of hydrogen gas from the re-
action system and to obtain completion of the reaction. When,
for instance, prereduced copper chromite is used as the spec-
ific dehydrogenation cataly~t, a reaction temperature of about
200C. is required and, therefore, a heavy aromatic solvent
with a minimum boiling point of about 200C. is used.
After completion of the dehydrogenation stage, the
cataly~t can be removed by filtration at a temperature of about
130C., or at a lower temperature, 95C. to 110C., by the
addition of a co-solvent such as dimethylformamide in which the
product 3,5-disubstituted pyrazole i~ more soluble. The fil-
trate i~ cooled, preferably to about 10C., and the 3,5-di-
~ _ 4 _
B
()455
~ubstituted pyraæole, prepared by the above reaction, is then
~eparated from the filtrate. Separation may be accomplished
by any convenient means, as for example, by centrifugation or
filtration.
A~ an alternative procedure, the dehydrogenation
2~
. ~
30:~
: .
- ~a-
~. `
.
,:
10~0455
1 mixture from the above reaction containing the 3,5-disubsti-
tuted pyrazole and the catalyst, can ~e employed directly
without separation in the preparation of l-alkyl-3,5-disub-
stituted pyrazole. This eliminates the need for a hot cata-
lyst filtration, because the 1-alkyl-3,5-disubstituted pyra-
zGle is extremely soluble in the reaction solvent, and the
catalyst can then be r~moved after the alkylation step merely
by room temperature filtration. The catalyst can then be re-
cycled to prepare another batch of 3,5-disubstituted pyrazole.
io As hereinabove mentioned, catalytic dehydrogenation
can also be carried out in a Cl-C4 alcohol, preferably meth- -~
anol or ethanol, employing palladium on carbon or platinum on
carbon as the catalyst. This procedure does not require dis-
tillation of a portion of the alcohol and subsitution thereof
with a solvent, such as xylene or mixed xylenes. However,
dehydrogenation in alcohol proceeds more slowly than it does
in the preferred co-solvent system, and product yields are
generally lower than those obtained with said system. These -
results are primarily due to the lower boiling point of the
alcohol, and to the greater solubility of 3,5-disubstituted
pyrazole in alcohol. After a hot filtration to remove the
catalyst from the reaction mixture, resultant mixture is cool-
ed to about 10C. The pyrazole precipitates and can be sep-
- ~ arated by filtration or centrifugation. If desired, water can
be added to the reaction mixture after separation of the cata-
lyst, to improve pyrazole precipitation and separation from
- the reaction mixture.
; The 3,5-disubstituted pyrazoles prepared in accord-
ance with the process of this invention have a variety of
.
uses, among which is the utilization thereof as intermediates
for the preparation of 1,2-dialkyl-3,5-disubstituted pyrazol-
ium salts, such as 1,2-dimethyl-3,5-diphenylpyrazolium methyl
sulfate. These pyrazolium salts are highly effective herbi-
_ 5 -
,;
. ~- ,:, ;, -- . .
~.. ()tiO455 : ~
1 cidal agents and are particularly effective for the selective
control of wild oats in the presence of small grains such as
barley, wheat, rye and rape.
As previously stated, resultant 3,5-disubstituted
pyrazole can be converted to a corresponding 1-alkyl-3,5-di-
substituted pyrazole by reacting it with an equimolar amount
or excess ~i.e. 1 to 1.5 r,loles) of an alkylating agent in the
presence of a solid, anhydrous, inorganic alkali metal base
and a non-aqueous, inert, organic solvent. The reaction is
carried out at a temperature between about 50C. and 175C.,
and preferably between 85C. and 120C.
Suitable alkylating reagents include alkyl halides, -~
dialkyl sulfates, alkyl phosphates, alkyl hydrogen sulfates,
or alkyl toluene sulfonates; wherein said alkyl groups con-
tain from 1 to 4 carbon atoms. Among the preferred alkylat-
ing reagents are alkyl halides, such as methyl, ethyl, _-
-propyl, isopropyl, n-butyl and isobutyl chlorides and bro-
mides; dialkyl sulfates, such as dimethyl sulfate and alkyl
toluene sulfonates, such as methyl _-toluene sulfonate.
Illustrative solvents which may be employed herein
are non-aqueous, inert, organic solvents, preferably selected
from aromatic hydrocarbons, such as toluene and xylene; ali-
phatic hydrocarbons such as hexane and heptane; ketones hav-
ing from 4 to 7 carbon atoms, such as methyl isobutyl ketone,
cyclohexanone, or the like; alcohols having from 2 to 8 carbon
atoms, and preferably 3 to 4 carbon atoms; dipolar aprotic
solvents, such as dimethyl sulfoxide, dimethyl formamide, acet-
onitrile, nitrobenzene, N,N-dimethylacetamide, tetrahydro-
sulfonate; ethylene dichloride; and alkoxyalkyl ethers, such
as dioxane and tetrahydrofuran.
Suitable bases are solid, anhydrous, inorganic,
alkali metal bases. They are strong bases, and preferably
selected from the group consisting of sodium hydroxide, po-
-- 6 --
10~0~55
l tassium hydroxide, sodium carbonate, potassium carbonate,
calcium oxide and calcium hydroxide. -
Conversion of the 3,5-disubstituted pyrazoles to
the 1-alkyl-3,5-disubstituted pyrazoles can be graphically
S illustrated as follows:
(II) ~ R2 + (R3)mQ ~ Ease ~ Rl_ ~ R2
N - N-H N - N
wherein Rl and R2 are as defined above in (I); R3 is an alkyl
radical of from l to 4 carbon atoms, Q is a radical selected -
from the group consisting of a halide, a sulfate, a phosphate,
toluene sulfonate and a hydrogen sulfate; and m represents àn
15 integer selected from l to 3. -
Resultant 1-alkyl-3,5-disubstituted pyrazole is
then readiiy converted to the hérbicidally active 1,2-dialkyl-
-3,5-disubstituted pyrazolium salt by quaternization of the
1-alkyl-3,5-disubstituted pyrazole.
Conversion of the l-alkyl-3,5-disubstituted pyra-
zole to the 1,2-dialkyl-3,5-disubstituted pyrazolium salt is
achieved by reacting the pyrazole with an equimolar amount
or a slight excess of an alkylating reagent (R4)mQ~ where
- ~ R4 is alkyl Cl-C4 and m and Q are as defined above. Alkyl-
ating reagents that can be used are selected from the group
consisting of alkyl halides, dialkyl sulfates, and alkyl tol-
uene sulfonates. They are used in equimolar amounts with the
pyrazole or in a slight excess, for example, from about l to
1.5 moles per mole of pyrazole. j ~ -
In general, the latter reaction is carried out in
the presence of a non-aqueous organic solvent, such as xylene
or in a mixture of inert organic solvents consisting of (a)
a chlorinated hydrocarbon solvent, and (b) an organic solvent
7 _
455
1 selected from the group oonsisting of aromatic hydrocarbons,
aliphatic hydrocarbons, ketones, alcohols, alkoxyalkyl ether~s,
dipolar aprotic solvents and cyclic ethers as defined above.
Preferred mixtures generally consist of from about 10% to
90%, preferably 25% to 75%, by volume of a solvent in which
the quaternized 3,5-disubstituted pyrazolium salt is rela-
tively insoluble, and from about 90% to 10%, preferably 75%
to 25%, of a solvent in which the quaternized 3,5-disubsti-
tuted pyrazolium salt is relatively soluble. Preferred co-
-solvent systems meet the above requirements as to percent
composition, and are selected from aromatic hydrocarbon sol-
vents in admixture with chlorinated hydrocarbon solvents or
aliphatic hydrocarbon solvents in admixture with chlorinated
hydrocarbon solvents. Particularly advantageous are xylene-
-ethylene dichloride mixtures. The latter compositions are
especially useful, since they provide a readily filterable,
flowable slurry from which the quaternized 3,5-disubstituted
pyrazolium salt is readily recovered. The use of the co-
-solvent system assures excellent yields of very high purity
product and avoids the production of mixtures of quaternized
3,5-disubstituted pyrazolium salts. This alkylation is car-
ried out in a manner which assures that the temperature of
the reaction mixture is generally maintained between,about
50C. and 175C., and preferably between 90C. and 110C.
The reaction mixture containing the pyrazolium
salt is cooled and thé pyrazolium salt is tllen separated from
the reaction mixture. Alternatively, the reaction mixture
may be heated with a tertiary-am'ine to destroy residual alkyl-
ating agent, cooled and then centrifuged or filtered to re-
cover the pyrazolium salt. Yet another alternative is to ex-
tract the pyrazolium salt with water from tlle above-mentioned
reaction mixture. The water solution thus obtained may then
be employed directly in the control of undesirable plant
-- 8 --
106V455
1 species.
The above reaction and the herbicidally effective
1,2-dialkyl-3,5-disubstituted pyrazolium salts, which can be
prepared by said reaction, is illustrated as follows: -
R2~R~ 1~ R2~R~ X
N N + (R4)mX ~ N ~~ N
R3 R,~ R~ m
.10
where Rl, R2, R3 and R4 are as described above; X represents
an anion having a charge from 1 to 3; and m is an integer
selected from 1, 2 and 3.
Illustrative of the anions which are suitable for
15 use in the present invention mav be mentioned, for example, -~
halides such as chloride, bromide or iodide; sulfate; hydro-
.
gen sulfate; methyl sulfate; benzene sulfonate; Cl-C4 alkoxy
benzene sulfonate; Cl-C4 alkyl benzene sulfonate, preferably
; a toluene sulfonate such as p-toluene sulfonate; phosphate ~
20 and methyl phosphates; and alkane sulfonate Cl-C4. - ~ -
The following examples illustrate the invention.
Unless otherwise specified, the parts are by weight and the
analyses are in percent.
~, , .
: ~ .
~ 25 -
,
. . .
- -
: .
,
_ 9 _
''
10~i0~55
EXAMPLE 1
The preparation of 3,5-diphenylpyrazole
Acetophenone (31.85 parts), benzaldehyde t28.13 parts)
and methanol (157.58 part~) are charged to a suitable reactor,
and 50% aqueou3 sodium hydroxide tlO,61 parts) is then added
at 20C. to 30C. The reaction muxture is stirred for 4 hours
at 20C. to 30C. After the hold period, the resultant chalcone
~lurry is made slightly acidic (pH 5 to 7) by the addition of
36% hydrochloride acid. The reaction mixture is cooled to -5C.
to 0C. Nitrogen i8 introduced over the reaction mixture, and
20.86 parts of 70~ hydrazine hydrate is added at a maximum temp-
èrature of 35C. After the hydrazine hydrate addition, the
reaction mixture is stirred at 20C. to 30C. for one hour.
Approximately 75% to 80% of the methanol i~ then distilled off
and replaced with mixed xylenes, The xylene solution is cooled
to 50C. to 60C. and washed twice with water to remove ~odium
chloride, methanol and unreacted hydrazine hydrate.
After the last water wash, 2.20 parts of 5% palladium
on carbon carbon catalyst i~ added under nitrogen, and the re-
2a action mixture heated to reflux [140C. to 144C.) and held at
reflux for 2 hours. A small amount of water i8 azeotropically
removed during the heat-up and the x~lene returned to the re-
actor. Hydrogen is evolved during the heat-up and during the
2-hour hold period at reflux. After the hold period, 15.0
2`5 part~ of dimethylformamide is added, and the catalyst removed
by a hot (120C.) filtration. The catalyst is washed with
xylene and then steamed to remoYe trace impuritie~ and recycled
for reuse. Water ~53.1 parts) i8 added to the catalyst-free
filtxate and the mixture cooled to 10C. 3,5-diphenylpyrazole
is iltered. About 43.2 part~ of 3,5-diphenylpyrazole (dry
--10--
. . -
10~0~55
basi~ is obtained~ This amounts to a 74% yield based on the
acetophenone reactant~
EXAMPLE 2
The procedure of Example l i~ repeated in every de-
tail except platinum on carbon i~ substituted for palladium oncarbon. Substantially the same results are obtained. In an-
other run, prereduced copper chromite is substituted for
palladium on carbon utilizing the procedure of Example 1.
However, approximately 0.5 part of prereduced copper chromite
per gram mole of acetophenone i8 utilized, and the dehydro-
genation i8 conducted in the presence of a high boiling aromatic
~olvent, PANASOL~AN-2, at a temperature of about 200C.
Following the above procedure, but ~ub~tituting the
appropriate ketone and aldehyde for acetophenone and ben-
zalde~yde, re~pectively, the following pyrazoles are obtaineda~' ~et forth in Table I below.
~Ofà0~5S
TABLE I
R R ! ~
\~L .`
Rl R2
2-chlorophenyl phenyl ;
3-chlorophenyl phenyl
4-fluorophenyl phenyl
2-methylphenyl phenyl
4-t-butylphenyl phenyl
2-hydroxyphenyl phenyl
3-methoxyphenyl phenyl
4-methylthiophenyl phenyl
3-methylsulfonyl- phenyl
phenyl .
~-chlorophenyl 3-methylphenyl
2-chlorophenyl 2-chlorophenyl
3-chlorophenyl 5-chlorophenyl
2-methylphenyl 2-methylphenyl
4-methoxyphenyl 4-methoxyphenyl
2-chlorophenyl 2-methoxyphenyl
3-fluorophenyl 3-fluorophenyl
2,4-dichlorophenyl 2,4-dichlorophenyl
4-cyanophenyl 4-cyanophenyl
3-carboxyphenyl phenyl
4-chloromethyl- 4-chloromethylphenyl
phenyl
~-carbomethoxy- phenyl
phenyl
- 12 -
iO~0455
TABLE_I (Continued)
. . __
, 1 R 2
3,4-dimethylphenyl 3,4-dimethylphenyl
2,4-dimethoxyphenyl 2,4-dimethoxyphenyl
4-chloro-3-methylphenyl 4-chloro-3-methylphenyl
3,5-dibromophenyl 3,5-dibromophenyl
EXAMPLE 7
The p~ ation of Q-(l-methyl-5-phenyl-3-pyrazolyl)phenol ~ ~-
A slurry of 5~ palladlum on carbon (o.6 part in
20 parts by volume of xylene) is added slowly to a cooled
(5C.) solution of o-(l-methyl-5-phenyl-2-pyrazolin-3-yl) -
phenol (10.5 parts) in 50 parts by volume of xylene, and
the resulting suspension heated at reflux. Periodically,
samples are removed for gas~ liquid chromatography (glc)
analysis.
When glc indlcates that all of the starting material
has been utilized, the reaction mixture is cooled and filtered,
and then is evaporated in vacuo to give an orange-brown oll
which slowly crystallizes. After drying thoroughly, a
product weighing 8,1 parts is obtained with melting point
90.5C. to 93C. This amounts to a yield of 78.2%, ba~ed
on the weight of o~ methyl-5-phenyl-2-pyrazollum-3-yl)
phenol.
~ , . - .
Analysis calculated for C16H14NzO: C, 76.78;
H, 5,64; N, 11.19. Found: C, 76.60; H, 5.72; N, 10.6~.
` EXAMPLE 4
.
The preparation of l-methyl-3,5-diphenylpyrazole
3 The procedure of Example 1 is followed in every
detail except that no dimethylformamide is added during the
dehydrogenation ~tep and the catalyst is not removed,
The reaction mixture is cooled to about 50C~J 2.42 parts
,
10~0~5S
of methyl alcohol and 11.3 parts of solid anhydrous sodium
hydroxide are added. The reaction mixture is heated to
95C. to 100C., and 29.8 parts of dimethyl sulfate are next
added. The reaction mixture ls heated at reflux for about
60 minutes, then cooled to 80C., and 82 parts of water are
added, Fifty percent aqueous sodium hydroxide are added to
bring the pH of the aqueous phase to between 10 and 11.
The reaction mixture is filtered to recover the spent catalyst.
There is no need to fllter hot, because the l-methyl-3,5-
diphenylpyrazole is extremely soluble in xylene. The
catalyst is washed with xylene, and water, and then recycled
to a subsequent dehydrogenation batch. The aqueous layer
is removed, the organic layer is washed with 82 parts or
water, and the aqueous layer is removed. The organic layer
contalns about 41 parts of 1-methyl-3,5-diphenylpyrazole which
amounts to 89.5~ yield based on 3,5-diphenylpyrazole.
EXAMPLE 5
The preparation of l-methyl-3,5-diphenylpyrazole
Five parts of 3,5-diphenylpyrazole are dissolved
in 25 parts (by volume) of methyl isobutyl ketone. Solid
anhydrous sodium hydroxide (1.1 parts) is added and the
mixture is heated to 90C. Dimethyl sulfate (3.43 parts)
is added and the mixture ls next heated to 112C. to 115C.
~25 The reaction mixture is sampled after 1.5 hours, and no un-
reacted 3,5-diphenylpyrazole i5 found to be present. The
reaction mixture i8 cooled to 50C., and 30 parts of water
are added. The pH ls next ad~usted to between 11 and 12 by
the addltion of aqueous sodium hydroxide. The organic layer
ls washed twice with 30 parts water. For yield determination
the methyl isobutyl ketone is removed in vacuo, producing
4.95 parts (93~ crude yield) of an oil which crystallizes
on cooling (melting point 52C. to 53C). Analysis of the
- 14 -
, . - . . . . . . . .
~0~0~55 :
product shows it to be 85.5~ pure as 1-methyl-3,5-diphenyl- -
pyrazole,
EXAMPLE 6
The p~eparation of l-methyl-3,5-diphenylpyrazole - -
Twenty parts of ~,5-diphenylpyrazole is dissolved
in 100 parts xylene containing 7.26 parts of solid anhydrous
sodium hydroxide. The reaction mixture is heated to 120C., ~
and 13.8 parts of dimethyl sulfate are added. The reflux l -
temperature drops to 95C., and after 15 minutes at 95C.,
a reactlon mixture sample indicates no unreacted 3,5-diphenyl-
pyrazole is remaining (tlc.) After 30 minutes, the reaction ~
mlxture ls cooled to 80C. and 50 parts of water are added. --
Flfty percent aqueous sodium hydroxide is added to bring pH
of aqueous phase to between 10 and 11. The organic layer is
washed twice with 50 parts of water. For yield determination
the xylene i~ removed in vacuo, producing 19,7 part8 of an
oll whlch crystalllzes on 8eedlng. Analysis of the product
shows it to be 98.5% pure. --
EXAMPLE 7
The preparation of 1,2-dimethyl-3,5-dlphenylpyrazolium methyl
sulfate
,~ .
A solution of 1 mole of 1-methyl-3,5-diphenyl-
pyrazole in xylene i~ prepared by following the procedure
of Example 4, above, About 75% of the xylene i~ di~tllled
off, and a quantity of ethylene dichloride equivalent to
the xylene remainin~ in the reaction mixture is added. The
reaction mixture i~ cooled to 60C., and 1.05 moles of
dlmethyl sulfate are then added and the mlxture is heated
to 105C. to 110C. and maintained at 105C. to 110C. for
about 4 hours The mixture is cooled to 50C. and triethyl-
amine (8 mole percent based on dimethyl sulfate) ls added.
The reaction mixture is stirred at 50C. for 30 minutes
The reaction mixture is cooled to room temperature and then
filtered and washed with xylene, then with acetone, and the
-- ].~ --
... . ~ ~ . . , ... . ... ... . . , , , . , , -
106045S
product drled. A 90~ yield of product is obtained.
EXAMPLE 8
Example 7 is repeated in every detail except
that 16 mole percent instead of 8 mole percent of tri-
ethylamine based on dimethyl ~ulfate is employed. It is
noted that a simllar yield of product is obtalned. ~-
EXAMPLE 9
There are reacted 12.5 parts of benzalacetophenone
and 3.1 parts (by volume) of hydrazine hydrate in methanol
to form 3,5-diphenyl-2-pyrazoline. To the latter ~s added
then 5~ palladium on carbon catalyst (2 parts) and the reaction
mixture is heated at reflux for 1 hour and 20 mlnutes. The
product, 3,5-diphenylpyrazole, is obtained in 97.8~ yield.
EXAMPLE 10
The procedure of Example 9 is repeated in every
detail except that 1.0 part catalyst is used and the solvent
is isopropanol, Following refluxing ~or 4 1/2 hours, 3,5-
diphenylpyrazole ls obtained in 90,7~ yield.
EXAMPLE 11
Benzalacetophenone (12.5 parts) is reacted w~th
hydrazine hydra~e (3.1 parts by volume) in methanol to
form 3,5-diphenyl-2-pyrazoline. Panaso ~ AN-2 (30 ml),
nitrobenzene (7.4 parts) and 5~ palladium on carbon catalyst
~- (2 parts) are then added and the mixture heated. Following
the distillation of methanol and water from the reaction
mixtureJ the temperature is raised to 200C. and held at
that temperature for 24 hours, The mixture is then cooled -
to 50C., filtered, and the catalyst bearing cake of 3,5- ;
diphenylpyrazole is 79,5%, m.p, 194C. to 199C,
EXAMPLE 12
The procedure of Example 11 is repeated, except
16
,. '
lV~0~55
that 5~ palladium on carbon catalys~ (2 parts) is substituted
for the platinum on carbon catalyst, and the reaction mixture
is held at 200C. for 20 hours. 3,5-Diphenylpyrazole is
obtained in 70.4~ yield.
EXAMPLE 13
The procedure of Example 12 is repeated, except
that no nitrobenzene is added to the reaction mixture and
the amount of 5~ palladium on carbon catalyst is reduced
to 0,1 part. Following a 6 1/4 hours hold at 200C., 3,5-
diphenylpyrazole is obtained in 78.7% yield.
EXAMPLE 14
The procedure of Example 13 is repeated, except
that Humble Aromatic 150 solvent is substituted for Panasol~
AN-2 in the dehydrogenation step. Following a 4 hours hold
at 200C " 3,5-diphenylpyrazole is obtained in 41,5~ yield.
EXAMPLE 15
The procedure of Example 14 is repeated, except
that the dehydrogenation step is carried out under a nitrogen
atmosphere and the hydrogen formed in the reaction is purged
with nitrogen. Following a 1 1/2 hours hold at 200C.,
3,5-diphenylpyrazole is obtained in 89.3% yield.
EXAMPLE 16
The procedure o~ Example 15 is repeated except
- the solvent used in the dehydrogenation step is toluene.
After 4 1/2 hours at reflux, 3,5-diphenylpyrazole is obtained
in 91.0% yield.
EXAMPLE 17
3,5-Diphenyl-2-pyrazoline (21.9 parts) is dissolved
in ethylene dichloride (75 parts by volume). There is next -
added 5~ palladium on carbon catalyst (~ parts containing
40~ water) is added and the mixture is heated at reflux for
8 hours. There is obtained 3,5-diphenylpyrazole i~ a 79.3%
yield whose melting point ranges ~rom 196C, to 200C.
,
- 17 -
lQ~0~55
EXAMPLE 18
To a suitable reaction vessel are added 42 parts
of benzalacetophenone which is slurried in 130 parts (by
volume) of methanol and 20 parts of water at room temperature.
I'he latter mixture is next purged with nitrogen and 13 parts
of 85% hydrazine hydrate are added rapidly to form 3,5-
diphenyl-2-pyrazoline. The mixture is heated to reflux and
105 parts of the methanol-water mixture is distilled,
130 parts of xylene are next added, the aqueous phase is
removed, and the organic phase is washed with water. There
is then added 0.2 part of 5~ Pd/alumina under N~ a nitrogen
blanket. The mixture is heated to reflux. Following a two
hour reflux, the mixture was cooled to 10C. The catalyst-
contalning solid ~,5-diphenylpyrazole is isolated by
filkration, washed with hexane and air-dried. ~,5-Diphenyl-
pyrazole melt~ng at 198 - 201.5C. was obtained in a 90.1%
yield,
EXAMPLE 19
The procedure of Example 18 is followed except
that 2 parts of 5% palladium on barium sulfate are used
in lieu of the palladium on alumina Example 18. Following
a 2 1/2 hour of reflux, unreacted 3,5-diphenyl-2-pyrazoline
is found to amount to 2.4~, and a 76.4% yield of 3,5-diphenyl-
pyrazole, melting at 198 - 201C. is obtained.
EXAMPLE 20
The procedure of Example 19 is followed except that
0.4 part palladium black ~100~ Pd) is used as the catalyst.
Following 4 hours reflux, unreacted 3,5-diphenyl-2-pyrazoline
is recovered in a yield of 1.1~, and a 88.9% yield of 3,5-
diphenylpyrazole melting at 197-201C. is obtained.
,
~ - 18 -
