CA1037048A - Catalytic dehydrogenation process for the preparation of 3,5-disubstituted pyrazoles - Google Patents
Catalytic dehydrogenation process for the preparation of 3,5-disubstituted pyrazolesInfo
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- CA1037048A CA1037048A CA207,577A CA207577A CA1037048A CA 1037048 A CA1037048 A CA 1037048A CA 207577 A CA207577 A CA 207577A CA 1037048 A CA1037048 A CA 1037048A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
Abstract
ABSTRACT OF THE DISCLOSURE
There is provided a process for the preparation of 3,5-disubstituted pyrazoles which involves:
(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 .alpha.,.beta.-unsaturated ketone, such as chalcone or a substituted chalcone, (b) the acidification of said a,.beta.-unsaturated ketone, follow-ed by treatment of the acidified reaction mixture with hydrazine to form a disubstituted pyrazoline, and (c) the catalytic dehydrogenation of said pyrazoline to yield the desired 3,5-disubstituted pyrazole.
There is provided a process for the preparation of 3,5-disubstituted pyrazoles which involves:
(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 .alpha.,.beta.-unsaturated ketone, such as chalcone or a substituted chalcone, (b) the acidification of said a,.beta.-unsaturated ketone, follow-ed by treatment of the acidified reaction mixture with hydrazine to form a disubstituted pyrazoline, and (c) the catalytic dehydrogenation of said pyrazoline to yield the desired 3,5-disubstituted pyrazole.
Description
7~
The pres.ent invention relates to a process for the manufacture of 3,5-disubstituted pyrazoles. ~ore particularly, the invention provides a method for the preparation of 3,5-di-substituted pyrazole ~aving the formula:
R2 ~ 1 N ~--N-H
wherein R~ nd ~2 is - ~
Z Z ., said Y, Y', Z and Z' each represents a member selected from the :~
group consisting of hydrogen, halogen, methylthio, methyl-sulfonyl, cyano, carboxyl, car~oalkoxy Cl-C4, hydroxy, alkyl ..
Cl-C4, haloalkyl Cl-C4 containing 1 to 4 halogen atoms and .. -10 alkoxy Cl-C4 which comprises the steps of: reacting approxim- .
ately equimolar amounts of a compound having the formula RlCOCH3 .. ~.
with a compound having the formula R2CHO, wherein Rl and R2 are .~
as defined above, in the presence of a base and a Cl-C4 !: .
alcoholic solvent at a temperature ranging between about 10C. ~
and 70C., acidifying said reaction mixture to a pH of 5 to 7, :.
treating the so-acidified reaction mixture with from about : ;
1.0 to 2.0 mole equivalents of hydrazine, adding to said : reaction mixture a catalyst selected from the group consisting ~: :
,.
of palladium on carbon, platinum on carbon and pre-reduced 20 copper chromite, heating said mixture to refluxing temperatures, -;.
and recovering the desired 3,5 disubstituted pyrazole in good .. .~.
yield and purity. .~
In general, the overall reaction can be illustrated .. ; :
graphically as follows~
~3~
o (I) RlCOCH3 ~ R2CHO ~ R2OEI=CHCRl -a methyl ketone a 1,3-disub- (1) mineral -~ an aldehyde stituted ,~_ acid, then unsaturated ketone (2) H2NNH2 ~I2 Rl ~ R2 ,~catalyst R1 ~ 2 N ~ N-H (dehydro- N N-H
genation) --3,5-disubstituted A disubstituted pyrazole pyrazoline wherein Rl is ~ ; R2 i~ ~ ; and Y, Y'~ Z and Z z' Z' each independently represent members selected from the group consisting of hydrogen, halogen, methylthio, me~hyl-sulfonyl, cyano, carboxyl, carboalkoxy Cl-C4, hydroxy, alkyl Cl-C4, haloalkyl Cl C4 containing 1 to 4 halogen atoms, and ~ .
alkoxy Cl-C4. : -,'. ', , ,. ... . .
: ,. :
",' ,, ~ :.
:. ~' ,. ' ' ~
. " ':: ' -' . ' , ' ~, ~,: ' : , .:: .. ' .
,.' .',, .
-la~
.: '' - ' ' .
; V, -"
~L037~14B
The term "halogen", as herein used, is intended to mean ~luorine, chlorine, iodine or bromine; however, fluorine, chlorine and bromine are preferre~. -The terms "alkyl" and "alkoxy" are intended to mean straight chain and branched chain alkyl and alkoxy, includ-ing straight and branched haloalkyl, and straight and branched -carboalkoxy.
In accordance with the process of this invention, ap-proximately equimolar amounts of the ketone, RlCOCH3, and the aldehyde, R2CHO, are charged to a reactor along with a quantity of a Cl-C4 alcohol, preferably methanol. Approxi-mately one-half mole of base per mole of ketone is then slowly added to the reaction mixture while maintaining the temperature thereof between about 10C. and 70C., and pre-ferably between 20C. and 30C.
Exemplary bases include, for instance, alkali metal Cl-C4 alkoxides, such as sodium or potassium methoxide, ethoxide, propoxide, butoxide, t-butoxide, and equivalents thereof, or aqueous sodium hydroxide or potassium hydroxide.
Aqueous sodium hydroxide is, however, generally preferred.
The aforementioned ketone-aldehyde mixture is stirred, 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 ~ -:: , phosphoric acid. In practice, it will usually be found that ,,- ,:
the mole ratio of acid required for pH adjustment will ap-proximate the mole ratio of base employed in the previous reaction.
Subsequent to acidi.fication, the reaction mixture is treated with at least one mole~equivalent; and preferably an excess, i.e., up to 100~ excess or 2 mole equivalents, ,~
~ - 2 -:
~0371D4L8 of hydrazine. The hydrazine employed may be anhydrous or in aqueous solution, and should be introduced into the re-action mixture in such manner as to maintain the temperature thereof below 70C. and, preferably, between 20C. and 30C.
Since the reaction is exothermic, cooling is generally re-quired to maintain the latter temperatures. Further, the re-action is preferably carried out in an inert atmosphere in order to exclude air from the reaction mixture and, thus, prevent any oxidation of the intermediate pyrazoline. This can be achieved by conducting said reaction under a blanket of an inert gas, such as nitrogen, helium, argon or carbon dioxide. In general, the hydrazine addition period should be relatively rapid, since prolonged additions result in lower product yield. It is a good practice to complete the hydrazine addition 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, under 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 preferred solvent is xylene or mixed xylenes. However, other solvents are suitable. Exemplary solvents include, for in-stance, (a) benzene, toluene, heavy aromatic solvents, such ~ 3a as PANASOL~ AN-2, AN-3 or AN-5, ESSO H~N~, SOCAL 44 L, and ;~ the like, which have a mixed aniline point above 30F. but -- 3 _ ~7~
not exceeding 95F., an aromatic content be-tween 60% and lOO~i and a specific gravity at 60/60F. betwéen 0.88 and 1.5; (b) cyclic ethers such as dioxane and tetrahydrofuran (THF); (c) polar aprotic solvents such as acetonitrile and dimethylformamide (D~F); or (d) chlorinated hydrocarbons, such as chloroform, perchloroethylene or ethylene dichloride.
After the alcohol solvent is removed by distillation, and the selected solvent from the above-mentioned group of sol-vents, preferably xylenes or mixed xylenes, is added, the reaction mixture is cooled to between 40C. and 70C., and washed with water to remove alkali metal salts, alcohol and any unreacted hydrazine. In the preferred procedure, a cata-lyst, such as platinum or palladium on carbon, or prereduced !
copper chromitei, is added to the reaction mixture while main-taining an inert gas 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 as a slurry.
The overall reaction mixture is then brought to re- ;
flux and residual water removed by azeotropic distillation.
Refluxing is continued while maintaining an inert yas 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 speci-fic dehydrogenation catalyst, a reaction temperature of about 200C. is requiredt and, therefore, a heavy aromatic solvent ;with a minimum boiling point of about 200C. is used.
After completion of the dehydrogenation stage, the catalyst 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 is more soluble.
~C~37a~;L8 The filtrate is cooled, preferably to about 10C., and the 3,5-disubstituted pyrazole, prepared by the above reaction, is then separated from the filtrate. Separation may be ac-complished by any convenient means, as for example, by cen-trifugation or filtration.
As an alternative procedure, the dehydrogenation mix-ture from the above reaction containing the 3,5-disubstituted pyrazole and the catalyst, can be employed directly without separation in the preparation of l-alkyl-3,5-disubstituted pyrazoleO This eliminates the need for a hot catalyst fil-tration, because the l-alkyl-3,5-disubstituted pyrazole is extremely soluble in the reaction solvent, and the catalyst can then be removed after the alkylation step merely by room ~;
temperature filtration. The catalyst can then be recycled to prepare another batch of 3,5-disubstituted pyrazole.
As hereinabove mentioned, catalytic dehydrogenation can also be carried out in a Cl-C4 alcohol, preferably metha-nol or ethanol, employing palladium on carbon or platinum on carbon as the catalyst. This procedure does not require distillation of a portion of the alcohol and substitution thereof with a solvent, such as xylene or mixed xylenes. How-ever, dehydrogenation in alcohol proceeds more slowly than it does in the preferred co-solvent system, and product yields are generaIly 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 catal~st from the reaction mixture, resultant mi~ture is cooled to about 10C. The pyrazole precipitates and can be separated by filtration or centrifugation. If de-sired, water can be added to the reaction mixture, after sepa-ration of the catalyst, to improve pyrazole precipitation ~
.',:
- 5 - ~ ~
~ai3Y~
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 intermedi-ates for the preparation of 1,2-dialkyl-3,5-disubstituted pyrazolium sa]ts, such as 1,2-dimethyl-3,5-diphenylpyrazolium methyl sulfate. These pyrazolium salts are highly effective herbicidal 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 l-alkyl-3,5 disubstituted pyrazole by reacting it with an equimolar amount or e~cess (i.e., 1 to 1.5 moles) 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, n-propyl, isopropyl, n-butyL and isobutyl chlorides and bro-mides; dialkyl sulates-, such as dimethyl sulfate and alkyl ; ~toluene sulfonates, such as methyl p-toluene suIfonate.
Illustrative solvents which may be employed herein are non-aqueous, inert, organic solvents, preferably se-;~ lected from aromatic hydrocarbons, such as toluene and xylene;
aliphatic hydrocarbons such as hexane and heptane; ketones having ~rom 4 to 7 carbon atoms, such as methyl isobutyl ke-tone, cyclohexanone, or the like; alcohols having from 2 to : : . ' ,'.
~iL03~
8 carbon atoms, and preferably 3 to 4 carbon atoms; dipolar aprotic solvents, such as dimethyl sulfoxide, dimethyl forma-mide, acetonitrile, nitrobenzene, N,N-dimethylacetamide, tetrahydrosulfolane; 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, potassium hydroxide, sodium carbonate, potassium carbonate, calcium oxide and calcium hydroxide.
Conversion of the 3,5-disubstituted pyrazoles to the l-alkyl-3,5-disubstituted pyrazoles can be graphically illustrated as follows:
(II) ~ a (R3)mQ + ~e ~ Rl--~
P~ . , ' ' .
wherein Rl and R2 are as defined above in (I); R~ is an alkyl radical of from 1 to 4 carbon atoms, Q is a radical :
selected from the groùp consisting of a halide, a sulfate, :
a phosphate, toluene sulfonate and a hydrogen sulfate; and m represents an integer selected from 1 to 3.
Resultant l-alkyl-3,5-disubstitu~ed pyrazole is then readily converted to the herbicidally active 1,2-dialkyl-3,5--disubstituted pyrazolium salt by quaternization of the l-alkyl-3,5-disubstituted pyrazole. .:.~ . :
Conversion of the l-alkyl-3,5-disubstituted pyrazole to the 1,2-dialky1-3,5 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. Alky-~: : lating reagents that can be used are selected from the group .:
.,: ~, _ 7 _ :
~LC3371)~
consisting of alkyl halides, dialkyl sul~ates, and alkyl toluene sulfonates. They are used in equimolar amounts with the pyrazole or in a slight excess, for example, from about 1 to 1.5 moles per mole of pyrazole.
In general, the latter reaction is carried out in the presence of a non-aqueous organic solvent, such as xylene or in a mixture o~ inert organic solvents consisting of (a) a chlorinated hydrocarbon solvent, and (b) an organic solvent selected from the group consisting of aromatic hydrocarbons, aliphatic hydrocarbons, ketones, alcohols, alkoxyalkyl ethers, 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-disubstitutéd pyrazollum 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 ~
..
carried 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.
~C~37~14B
The reaction mixture containing the pyrazolium salt ls cooled and the pyrazolium salt then separated from the reaction mixture. Alternatively, the reaction mixture may be heated with a tertiary-amine to de~troy residual alkylaking agent, cooled and the centrifuged or filtered to recover the pyrazollum ~alt, Yet another alternative i~ to extract the pyrazolium salt with water ~rom the above-mentioned reaction mixture. The water solution thus obtained may then be employed directly in the control of undesirable plant species.
The above reaction and the herblcidally e~fective 1,2-dialkyl-3,5-disubstituted pyrazolium salts, which can be prepared by said reaction, ls illustrated as ~ollows:
R2 ~ Rl + (R~)mX ~ ¦ R2 ~ 1 X
N N N N
R9 _ m 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 o~ the anions which are suitable for ~` -use in the present invention may be mentioned; ~or example, ~ -halides such as chloride~ bromide or iodide; sul~ate;
hydrogen sul~ate; methyl sulfate; benzene sul~onate; C -C ;
alkoxy benzene sulfonate; Cl-C4 alkyl benzene sul~onate, preferably a toluene sulfonate such a~ p-toluene sulfonate; ~
pho~phate and methyl pho~phates; and alkane ~ul~onate Cl-C4. ~ ~ !
The ~ollowing examp]es are presented primarlly for purposes o~ illustrating more specific details o~ the in-vention which are not to be taken a~ limitative Unless otherwlse speci~ied, the parts are by weight and the analysis -~are ln percent.
. - _ 9 _ ~,' ~, " ,.
~3701~
EXAMPL~ 1 The preparation of 3,5-diphenylpyrazole Acetophenone (31.85 parts), benzaldehyde (28.13 parts) and methanol (157.58 parts) are charged to a suitable reactor, and 50% aqueous sodium hydroxide (10.61 parts) is then added at 20~C. to 30C. The reaction mixture is stirred for 4 hours at 20C. to 30C. After the hold period, the resultant chalcone slurry 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 is introduced over the reaction mixture, and 20.86 parts of 70%
hydrazine hydrate is added at a maximum temperature 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 is then distilled off and re-placed with mixed xylenes. The xylene solution ls cooled to 50C. to 60C. and washed twice with water to remove sodium chloride, methanol and unreacted hydrazine hydrate.
After the last water wash, 2.20 parts of 5% palladi-um on carbon catalyst is added under nitrogen, and the re-action mixture heated to reflux ~140C. to 144~C.) and held at reflux for 2 hours. A small amount of water is azeotro-phically removed during the heat-up and the xylene returned to the reactor. Hydrogen is evolved during the heat-up and during the 2-hour hold period at reflux. After the hold period, 15.0 parts of dimethylformamide is added and the catalyst removed by a hot (120C.)i filtration. The catalyst is washed with xylene and then steamed to remove trace im-purities and recycled for reuse. Water (53.1 parts) is added to the catalyst-free filtrate and the mi~ture cooled to 10C. 3,5-diphenylpyrazole is filtered. About 43.2 parts : , ~!~137~
of 3,5-diphenylpyrazole (dry basis) is obtained. This amounts to a 74% yield based on the acetophenone reactant.
The procedure of Example 1 is repeated in every detail except platinum on carbon is substituted for palla-dium on carbon. Substantially the same results are obtained.
In another 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 is utilized, and the dehydrogenation is conducted in the presence of a high boil-ing aromatic solvent, PANASOL~ AN-2, at a temperature of about 200C.
:
Following the above procedure, but substituting -the appropriate ketone and aldehyde for acetophenone and benzaIdehyde, respectively, the following pyrazoles are ob-tained as set forth in Table I below.
: ' :
:
~ ~ 25 ~
~ , . . .
~ . ~ . . .
~ 30 :: : . ':' ~L~3~
~ABLE I
R R
~ ~ H
Rl I R2 : _ _
The pres.ent invention relates to a process for the manufacture of 3,5-disubstituted pyrazoles. ~ore particularly, the invention provides a method for the preparation of 3,5-di-substituted pyrazole ~aving the formula:
R2 ~ 1 N ~--N-H
wherein R~ nd ~2 is - ~
Z Z ., said Y, Y', Z and Z' each represents a member selected from the :~
group consisting of hydrogen, halogen, methylthio, methyl-sulfonyl, cyano, carboxyl, car~oalkoxy Cl-C4, hydroxy, alkyl ..
Cl-C4, haloalkyl Cl-C4 containing 1 to 4 halogen atoms and .. -10 alkoxy Cl-C4 which comprises the steps of: reacting approxim- .
ately equimolar amounts of a compound having the formula RlCOCH3 .. ~.
with a compound having the formula R2CHO, wherein Rl and R2 are .~
as defined above, in the presence of a base and a Cl-C4 !: .
alcoholic solvent at a temperature ranging between about 10C. ~
and 70C., acidifying said reaction mixture to a pH of 5 to 7, :.
treating the so-acidified reaction mixture with from about : ;
1.0 to 2.0 mole equivalents of hydrazine, adding to said : reaction mixture a catalyst selected from the group consisting ~: :
,.
of palladium on carbon, platinum on carbon and pre-reduced 20 copper chromite, heating said mixture to refluxing temperatures, -;.
and recovering the desired 3,5 disubstituted pyrazole in good .. .~.
yield and purity. .~
In general, the overall reaction can be illustrated .. ; :
graphically as follows~
~3~
o (I) RlCOCH3 ~ R2CHO ~ R2OEI=CHCRl -a methyl ketone a 1,3-disub- (1) mineral -~ an aldehyde stituted ,~_ acid, then unsaturated ketone (2) H2NNH2 ~I2 Rl ~ R2 ,~catalyst R1 ~ 2 N ~ N-H (dehydro- N N-H
genation) --3,5-disubstituted A disubstituted pyrazole pyrazoline wherein Rl is ~ ; R2 i~ ~ ; and Y, Y'~ Z and Z z' Z' each independently represent members selected from the group consisting of hydrogen, halogen, methylthio, me~hyl-sulfonyl, cyano, carboxyl, carboalkoxy Cl-C4, hydroxy, alkyl Cl-C4, haloalkyl Cl C4 containing 1 to 4 halogen atoms, and ~ .
alkoxy Cl-C4. : -,'. ', , ,. ... . .
: ,. :
",' ,, ~ :.
:. ~' ,. ' ' ~
. " ':: ' -' . ' , ' ~, ~,: ' : , .:: .. ' .
,.' .',, .
-la~
.: '' - ' ' .
; V, -"
~L037~14B
The term "halogen", as herein used, is intended to mean ~luorine, chlorine, iodine or bromine; however, fluorine, chlorine and bromine are preferre~. -The terms "alkyl" and "alkoxy" are intended to mean straight chain and branched chain alkyl and alkoxy, includ-ing straight and branched haloalkyl, and straight and branched -carboalkoxy.
In accordance with the process of this invention, ap-proximately equimolar amounts of the ketone, RlCOCH3, and the aldehyde, R2CHO, are charged to a reactor along with a quantity of a Cl-C4 alcohol, preferably methanol. Approxi-mately one-half mole of base per mole of ketone is then slowly added to the reaction mixture while maintaining the temperature thereof between about 10C. and 70C., and pre-ferably between 20C. and 30C.
Exemplary bases include, for instance, alkali metal Cl-C4 alkoxides, such as sodium or potassium methoxide, ethoxide, propoxide, butoxide, t-butoxide, and equivalents thereof, or aqueous sodium hydroxide or potassium hydroxide.
Aqueous sodium hydroxide is, however, generally preferred.
The aforementioned ketone-aldehyde mixture is stirred, 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 ~ -:: , phosphoric acid. In practice, it will usually be found that ,,- ,:
the mole ratio of acid required for pH adjustment will ap-proximate the mole ratio of base employed in the previous reaction.
Subsequent to acidi.fication, the reaction mixture is treated with at least one mole~equivalent; and preferably an excess, i.e., up to 100~ excess or 2 mole equivalents, ,~
~ - 2 -:
~0371D4L8 of hydrazine. The hydrazine employed may be anhydrous or in aqueous solution, and should be introduced into the re-action mixture in such manner as to maintain the temperature thereof below 70C. and, preferably, between 20C. and 30C.
Since the reaction is exothermic, cooling is generally re-quired to maintain the latter temperatures. Further, the re-action is preferably carried out in an inert atmosphere in order to exclude air from the reaction mixture and, thus, prevent any oxidation of the intermediate pyrazoline. This can be achieved by conducting said reaction under a blanket of an inert gas, such as nitrogen, helium, argon or carbon dioxide. In general, the hydrazine addition period should be relatively rapid, since prolonged additions result in lower product yield. It is a good practice to complete the hydrazine addition 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, under 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 preferred solvent is xylene or mixed xylenes. However, other solvents are suitable. Exemplary solvents include, for in-stance, (a) benzene, toluene, heavy aromatic solvents, such ~ 3a as PANASOL~ AN-2, AN-3 or AN-5, ESSO H~N~, SOCAL 44 L, and ;~ the like, which have a mixed aniline point above 30F. but -- 3 _ ~7~
not exceeding 95F., an aromatic content be-tween 60% and lOO~i and a specific gravity at 60/60F. betwéen 0.88 and 1.5; (b) cyclic ethers such as dioxane and tetrahydrofuran (THF); (c) polar aprotic solvents such as acetonitrile and dimethylformamide (D~F); or (d) chlorinated hydrocarbons, such as chloroform, perchloroethylene or ethylene dichloride.
After the alcohol solvent is removed by distillation, and the selected solvent from the above-mentioned group of sol-vents, preferably xylenes or mixed xylenes, is added, the reaction mixture is cooled to between 40C. and 70C., and washed with water to remove alkali metal salts, alcohol and any unreacted hydrazine. In the preferred procedure, a cata-lyst, such as platinum or palladium on carbon, or prereduced !
copper chromitei, is added to the reaction mixture while main-taining an inert gas 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 as a slurry.
The overall reaction mixture is then brought to re- ;
flux and residual water removed by azeotropic distillation.
Refluxing is continued while maintaining an inert yas 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 speci-fic dehydrogenation catalyst, a reaction temperature of about 200C. is requiredt and, therefore, a heavy aromatic solvent ;with a minimum boiling point of about 200C. is used.
After completion of the dehydrogenation stage, the catalyst 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 is more soluble.
~C~37a~;L8 The filtrate is cooled, preferably to about 10C., and the 3,5-disubstituted pyrazole, prepared by the above reaction, is then separated from the filtrate. Separation may be ac-complished by any convenient means, as for example, by cen-trifugation or filtration.
As an alternative procedure, the dehydrogenation mix-ture from the above reaction containing the 3,5-disubstituted pyrazole and the catalyst, can be employed directly without separation in the preparation of l-alkyl-3,5-disubstituted pyrazoleO This eliminates the need for a hot catalyst fil-tration, because the l-alkyl-3,5-disubstituted pyrazole is extremely soluble in the reaction solvent, and the catalyst can then be removed after the alkylation step merely by room ~;
temperature filtration. The catalyst can then be recycled to prepare another batch of 3,5-disubstituted pyrazole.
As hereinabove mentioned, catalytic dehydrogenation can also be carried out in a Cl-C4 alcohol, preferably metha-nol or ethanol, employing palladium on carbon or platinum on carbon as the catalyst. This procedure does not require distillation of a portion of the alcohol and substitution thereof with a solvent, such as xylene or mixed xylenes. How-ever, dehydrogenation in alcohol proceeds more slowly than it does in the preferred co-solvent system, and product yields are generaIly 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 catal~st from the reaction mixture, resultant mi~ture is cooled to about 10C. The pyrazole precipitates and can be separated by filtration or centrifugation. If de-sired, water can be added to the reaction mixture, after sepa-ration of the catalyst, to improve pyrazole precipitation ~
.',:
- 5 - ~ ~
~ai3Y~
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 intermedi-ates for the preparation of 1,2-dialkyl-3,5-disubstituted pyrazolium sa]ts, such as 1,2-dimethyl-3,5-diphenylpyrazolium methyl sulfate. These pyrazolium salts are highly effective herbicidal 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 l-alkyl-3,5 disubstituted pyrazole by reacting it with an equimolar amount or e~cess (i.e., 1 to 1.5 moles) 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, n-propyl, isopropyl, n-butyL and isobutyl chlorides and bro-mides; dialkyl sulates-, such as dimethyl sulfate and alkyl ; ~toluene sulfonates, such as methyl p-toluene suIfonate.
Illustrative solvents which may be employed herein are non-aqueous, inert, organic solvents, preferably se-;~ lected from aromatic hydrocarbons, such as toluene and xylene;
aliphatic hydrocarbons such as hexane and heptane; ketones having ~rom 4 to 7 carbon atoms, such as methyl isobutyl ke-tone, cyclohexanone, or the like; alcohols having from 2 to : : . ' ,'.
~iL03~
8 carbon atoms, and preferably 3 to 4 carbon atoms; dipolar aprotic solvents, such as dimethyl sulfoxide, dimethyl forma-mide, acetonitrile, nitrobenzene, N,N-dimethylacetamide, tetrahydrosulfolane; 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, potassium hydroxide, sodium carbonate, potassium carbonate, calcium oxide and calcium hydroxide.
Conversion of the 3,5-disubstituted pyrazoles to the l-alkyl-3,5-disubstituted pyrazoles can be graphically illustrated as follows:
(II) ~ a (R3)mQ + ~e ~ Rl--~
P~ . , ' ' .
wherein Rl and R2 are as defined above in (I); R~ is an alkyl radical of from 1 to 4 carbon atoms, Q is a radical :
selected from the groùp consisting of a halide, a sulfate, :
a phosphate, toluene sulfonate and a hydrogen sulfate; and m represents an integer selected from 1 to 3.
Resultant l-alkyl-3,5-disubstitu~ed pyrazole is then readily converted to the herbicidally active 1,2-dialkyl-3,5--disubstituted pyrazolium salt by quaternization of the l-alkyl-3,5-disubstituted pyrazole. .:.~ . :
Conversion of the l-alkyl-3,5-disubstituted pyrazole to the 1,2-dialky1-3,5 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. Alky-~: : lating reagents that can be used are selected from the group .:
.,: ~, _ 7 _ :
~LC3371)~
consisting of alkyl halides, dialkyl sul~ates, and alkyl toluene sulfonates. They are used in equimolar amounts with the pyrazole or in a slight excess, for example, from about 1 to 1.5 moles per mole of pyrazole.
In general, the latter reaction is carried out in the presence of a non-aqueous organic solvent, such as xylene or in a mixture o~ inert organic solvents consisting of (a) a chlorinated hydrocarbon solvent, and (b) an organic solvent selected from the group consisting of aromatic hydrocarbons, aliphatic hydrocarbons, ketones, alcohols, alkoxyalkyl ethers, 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-disubstitutéd pyrazollum 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 ~
..
carried 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.
~C~37~14B
The reaction mixture containing the pyrazolium salt ls cooled and the pyrazolium salt then separated from the reaction mixture. Alternatively, the reaction mixture may be heated with a tertiary-amine to de~troy residual alkylaking agent, cooled and the centrifuged or filtered to recover the pyrazollum ~alt, Yet another alternative i~ to extract the pyrazolium salt with water ~rom the above-mentioned reaction mixture. The water solution thus obtained may then be employed directly in the control of undesirable plant species.
The above reaction and the herblcidally e~fective 1,2-dialkyl-3,5-disubstituted pyrazolium salts, which can be prepared by said reaction, ls illustrated as ~ollows:
R2 ~ Rl + (R~)mX ~ ¦ R2 ~ 1 X
N N N N
R9 _ m 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 o~ the anions which are suitable for ~` -use in the present invention may be mentioned; ~or example, ~ -halides such as chloride~ bromide or iodide; sul~ate;
hydrogen sul~ate; methyl sulfate; benzene sul~onate; C -C ;
alkoxy benzene sulfonate; Cl-C4 alkyl benzene sul~onate, preferably a toluene sulfonate such a~ p-toluene sulfonate; ~
pho~phate and methyl pho~phates; and alkane ~ul~onate Cl-C4. ~ ~ !
The ~ollowing examp]es are presented primarlly for purposes o~ illustrating more specific details o~ the in-vention which are not to be taken a~ limitative Unless otherwlse speci~ied, the parts are by weight and the analysis -~are ln percent.
. - _ 9 _ ~,' ~, " ,.
~3701~
EXAMPL~ 1 The preparation of 3,5-diphenylpyrazole Acetophenone (31.85 parts), benzaldehyde (28.13 parts) and methanol (157.58 parts) are charged to a suitable reactor, and 50% aqueous sodium hydroxide (10.61 parts) is then added at 20~C. to 30C. The reaction mixture is stirred for 4 hours at 20C. to 30C. After the hold period, the resultant chalcone slurry 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 is introduced over the reaction mixture, and 20.86 parts of 70%
hydrazine hydrate is added at a maximum temperature 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 is then distilled off and re-placed with mixed xylenes. The xylene solution ls cooled to 50C. to 60C. and washed twice with water to remove sodium chloride, methanol and unreacted hydrazine hydrate.
After the last water wash, 2.20 parts of 5% palladi-um on carbon catalyst is added under nitrogen, and the re-action mixture heated to reflux ~140C. to 144~C.) and held at reflux for 2 hours. A small amount of water is azeotro-phically removed during the heat-up and the xylene returned to the reactor. Hydrogen is evolved during the heat-up and during the 2-hour hold period at reflux. After the hold period, 15.0 parts of dimethylformamide is added and the catalyst removed by a hot (120C.)i filtration. The catalyst is washed with xylene and then steamed to remove trace im-purities and recycled for reuse. Water (53.1 parts) is added to the catalyst-free filtrate and the mi~ture cooled to 10C. 3,5-diphenylpyrazole is filtered. About 43.2 parts : , ~!~137~
of 3,5-diphenylpyrazole (dry basis) is obtained. This amounts to a 74% yield based on the acetophenone reactant.
The procedure of Example 1 is repeated in every detail except platinum on carbon is substituted for palla-dium on carbon. Substantially the same results are obtained.
In another 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 is utilized, and the dehydrogenation is conducted in the presence of a high boil-ing aromatic solvent, PANASOL~ AN-2, at a temperature of about 200C.
:
Following the above procedure, but substituting -the appropriate ketone and aldehyde for acetophenone and benzaIdehyde, respectively, the following pyrazoles are ob-tained as set forth in Table I below.
: ' :
:
~ ~ 25 ~
~ , . . .
~ . ~ . . .
~ 30 :: : . ':' ~L~3~
~ABLE I
R R
~ ~ H
Rl I R2 : _ _
2-chlorophenyl phenyl
3-chlorophenyl phenyl
4-fluorophenyl phenyl 2-methylphenyl phenyl 4-t-butylphenyl phenyl 2-hydroxyphenyl phenyl ~::
3-metho~yphenyl phenyl -: ~
4-methylthlophenyl phenyl . .
3-methyl~ulfonyl- phenyl . --phenyl - ~ .
2-chlorophenyl 3-methylphenyl .
2-chlorophenyl 2-chlorophenyl :~
3-chlorophenyl 5-chlorophenyl 2-methylphenyl 2-methylphenyl ::
4-methoxyphenyl 4-methoxyphenyl :-2-chlorophenyl 2-methoxyphenyl 3-~luorophenyl 3-~luorophenyl 2l4-dichlorophenyl 29 4-dichlorophenyl 4-cyanophenyl 4-cyanophenyl -3-carboxyphenyl phenyl .:
4-chloromethyl- 4-chloromethylphenyl phenyl 3-carbomethoxy- phenyl phenyl - _ .
- 12 - ~-` `-,.. ~::
... .
~03~4~
TABLE I (Continued) . ~ - - Rz --~-~~-~--~~~-~---.. . . __ .
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 ~.. ~ . .................. . . .. _ .. _ __ , , .
.
The_preparation of Q-(l-methyl-5-phenyl-3-pyrazolyl)phenol . _ :
A slurry of 5~ palladium on carbon (o.6 part in 20 pQrts by volume of xylene) is added 310wly 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 re~ulting suspension heated at reflux. PeriodicallyJ
samples are removed for gas, liquid chromatography (glc) analysis. -~
When glc indicates that all of the starting material ; ~
has been utilized, the reaction mixture is cooled and filtered, ~ -and then i~ evaporated in vacuo to give an orange-brown oil -which slowly crystallizes, After drying thoroughly~ a product weighing 8.1 parts is obtained with melting point - ~-90,5C. to 9~C. This amounts to a yield of 78.2~, ba~ed on the weight of o-(l-methyl-5-phenyl-2-pyrazolium-3-yl) ~5 phenol, ~ -Analysis calculated for C16H14N20: C, 76-78;
H~ 5,64; NJ 11.19. Found: C, 76.60; Hz 5,72; N, 10,63. -EXAMPLE 4 -~
. .
The preparation o~ l-methyl-3,5-diphenylpyrazole 3~ The procedure Or Example 1 is followed in every ~',,'.A.~,'.'"~ ~' dekall except that no dimethylfo~mamide is added during the dehydrogenation ~tep and the catalyst is not removed. --The reaction mixture i~ coolecl to about 50C, J 2.42 parts ~ 13 - -~b37~4~
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 is heated at reflux for about 60 minutes, then coolPd 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 filter hot, bécause the 1-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 of water, and the aqueous layer is removed. The organic layer contains about 41 parts of 1-methyl-3,5-di-phenylpyrazole which amounts to 89.5~ yield based on 3,5--diphenylpyrazole.
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 an-hydrous sodium hydroxide (1.1 parts) is added and the mix-ture is heated to 90C. Dimethyl sulfate (3.43 parts) is added and the mixture is next heated to 112C. to 115C.
2S The reaction mixture is sampled after 1.5 hours, and no un-reacted 3,5-diphenylpyrazole is found to be pre~ent~ The reaction mixture is cooled to 50C., and 30 parts of water ',5 are added. The pH is next adjusted to between 11 and 12 by the addition of aqueous sodium hydroxide. The organic layer is washed twice with 30 parts water. For yield determination the methyl isobutyl ketone is removed ln vacuo, producing ~L03~4B
4.95 parts ~93% crude yield) of an oil which crystallizes on cooling (melting point 52C. to 53C.). Analysis of the product shows it to be 85.5% pure as 1-methyl-3,5-di-phenylpyrazole.
The preparation of l-methyl-3,5-diphenylpyrazole -Twenty parts of 3,5-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 temperature drops to 95C., and after 15 minutes at 95C., a reaction mixture sample indicates no unreacted 3,5-diphenyl-pyrazole is remaining (tlc.). After 30 minutes, the reaction mixture is cooled to 80C. and 50 parts of water are added.
Fifty 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 determina-tion the xylene is removed ln vacuo, producing 19.7 parts of an oil which crystallizes on seeding. Analysis of the prod-uct shows it to be 98.5% pure.
. ., The preparation of 1,2-dimethyl-3,5-diphenylpyrazolium methyl sulfate A solution of 1 mole of 1-methyl-3,5-diphenyl-pyra-zole in xylene is prepared by following the procedure of ~-Example 4, above. About 75% of the xylene is distilled off, and a quantity of ethylene dichloride equivalent to the xy- -lene remaining in the reaction mixture is added. The re-action mixture is cooled to 60C., and 1.05 moles of ~i-methyl sulfate are then added and the mixture is heated to 105C. to 110C. and maintained at 105C. to 110C~ for about 4 hours. The mixture is cooled to 50C. and triethyl-~1370gl~3 amine (8 mole percent based on dimethyl sulfate) is 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 product dried. A 90~ yield of product is obtained.
Example 7 is repeated in every detail except that 16 mole percent instead of 8 mole percent of triethylamine based on dimethyl sulfate is employed. It is noted that a similar yield of product is obtained.
x,~
:~ , ;30 ' ': , ., - 16 - -~
. -
3-metho~yphenyl phenyl -: ~
4-methylthlophenyl phenyl . .
3-methyl~ulfonyl- phenyl . --phenyl - ~ .
2-chlorophenyl 3-methylphenyl .
2-chlorophenyl 2-chlorophenyl :~
3-chlorophenyl 5-chlorophenyl 2-methylphenyl 2-methylphenyl ::
4-methoxyphenyl 4-methoxyphenyl :-2-chlorophenyl 2-methoxyphenyl 3-~luorophenyl 3-~luorophenyl 2l4-dichlorophenyl 29 4-dichlorophenyl 4-cyanophenyl 4-cyanophenyl -3-carboxyphenyl phenyl .:
4-chloromethyl- 4-chloromethylphenyl phenyl 3-carbomethoxy- phenyl phenyl - _ .
- 12 - ~-` `-,.. ~::
... .
~03~4~
TABLE I (Continued) . ~ - - Rz --~-~~-~--~~~-~---.. . . __ .
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 ~.. ~ . .................. . . .. _ .. _ __ , , .
.
The_preparation of Q-(l-methyl-5-phenyl-3-pyrazolyl)phenol . _ :
A slurry of 5~ palladium on carbon (o.6 part in 20 pQrts by volume of xylene) is added 310wly 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 re~ulting suspension heated at reflux. PeriodicallyJ
samples are removed for gas, liquid chromatography (glc) analysis. -~
When glc indicates that all of the starting material ; ~
has been utilized, the reaction mixture is cooled and filtered, ~ -and then i~ evaporated in vacuo to give an orange-brown oil -which slowly crystallizes, After drying thoroughly~ a product weighing 8.1 parts is obtained with melting point - ~-90,5C. to 9~C. This amounts to a yield of 78.2~, ba~ed on the weight of o-(l-methyl-5-phenyl-2-pyrazolium-3-yl) ~5 phenol, ~ -Analysis calculated for C16H14N20: C, 76-78;
H~ 5,64; NJ 11.19. Found: C, 76.60; Hz 5,72; N, 10,63. -EXAMPLE 4 -~
. .
The preparation o~ l-methyl-3,5-diphenylpyrazole 3~ The procedure Or Example 1 is followed in every ~',,'.A.~,'.'"~ ~' dekall except that no dimethylfo~mamide is added during the dehydrogenation ~tep and the catalyst is not removed. --The reaction mixture i~ coolecl to about 50C, J 2.42 parts ~ 13 - -~b37~4~
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 is heated at reflux for about 60 minutes, then coolPd 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 filter hot, bécause the 1-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 of water, and the aqueous layer is removed. The organic layer contains about 41 parts of 1-methyl-3,5-di-phenylpyrazole which amounts to 89.5~ yield based on 3,5--diphenylpyrazole.
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 an-hydrous sodium hydroxide (1.1 parts) is added and the mix-ture is heated to 90C. Dimethyl sulfate (3.43 parts) is added and the mixture is next heated to 112C. to 115C.
2S The reaction mixture is sampled after 1.5 hours, and no un-reacted 3,5-diphenylpyrazole is found to be pre~ent~ The reaction mixture is cooled to 50C., and 30 parts of water ',5 are added. The pH is next adjusted to between 11 and 12 by the addition of aqueous sodium hydroxide. The organic layer is washed twice with 30 parts water. For yield determination the methyl isobutyl ketone is removed ln vacuo, producing ~L03~4B
4.95 parts ~93% crude yield) of an oil which crystallizes on cooling (melting point 52C. to 53C.). Analysis of the product shows it to be 85.5% pure as 1-methyl-3,5-di-phenylpyrazole.
The preparation of l-methyl-3,5-diphenylpyrazole -Twenty parts of 3,5-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 temperature drops to 95C., and after 15 minutes at 95C., a reaction mixture sample indicates no unreacted 3,5-diphenyl-pyrazole is remaining (tlc.). After 30 minutes, the reaction mixture is cooled to 80C. and 50 parts of water are added.
Fifty 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 determina-tion the xylene is removed ln vacuo, producing 19.7 parts of an oil which crystallizes on seeding. Analysis of the prod-uct shows it to be 98.5% pure.
. ., The preparation of 1,2-dimethyl-3,5-diphenylpyrazolium methyl sulfate A solution of 1 mole of 1-methyl-3,5-diphenyl-pyra-zole in xylene is prepared by following the procedure of ~-Example 4, above. About 75% of the xylene is distilled off, and a quantity of ethylene dichloride equivalent to the xy- -lene remaining in the reaction mixture is added. The re-action mixture is cooled to 60C., and 1.05 moles of ~i-methyl sulfate are then added and the mixture is heated to 105C. to 110C. and maintained at 105C. to 110C~ for about 4 hours. The mixture is cooled to 50C. and triethyl-~1370gl~3 amine (8 mole percent based on dimethyl sulfate) is 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 product dried. A 90~ yield of product is obtained.
Example 7 is repeated in every detail except that 16 mole percent instead of 8 mole percent of triethylamine based on dimethyl sulfate is employed. It is noted that a similar yield of product is obtained.
x,~
:~ , ;30 ' ': , ., - 16 - -~
. -
Claims (11)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A method for the preparation of 3,5-disubstituted pyrazole having the formula:
wherein R1 is and R2 is said Y, Y', Z and Z' each represents a member selected from the group consisting of hydrogen, halogen, methylthio, methylsul-fonyl, cyano, carboxyl, carboalkoxy C1-C4, hydroxy, alkyl C1-C4, haloalkyl C1-C4 containing 1 to 4 halogen atoms and alkoxy C1-C4 which comprises the steps of: reacting approxim-ately equimolar amounts of a compound having the formula R1COCH3 with a compound having the formula R2CHO, wherein R1 and R2 are as defined above, in the presence of a base and a C1-C4 alcoholic solvent at a temperature ranging between about 10°C. and 70°C., acidifying said reaction mixture to a pH of 5 to 7, treating the so-acidified reaction mixture with from about 1.0 to 2.0 mole equivalents of hydrazine, adding to said reaction mixture a catalyst selected from the group consisting of palladium on carbon, platinum on carbon and pre-reduced copper chromite, heating said mixture to refluxing temperatures, and recovering the desired 3,5-disubstituted pyrazole in good yield and purity.
wherein R1 is and R2 is said Y, Y', Z and Z' each represents a member selected from the group consisting of hydrogen, halogen, methylthio, methylsul-fonyl, cyano, carboxyl, carboalkoxy C1-C4, hydroxy, alkyl C1-C4, haloalkyl C1-C4 containing 1 to 4 halogen atoms and alkoxy C1-C4 which comprises the steps of: reacting approxim-ately equimolar amounts of a compound having the formula R1COCH3 with a compound having the formula R2CHO, wherein R1 and R2 are as defined above, in the presence of a base and a C1-C4 alcoholic solvent at a temperature ranging between about 10°C. and 70°C., acidifying said reaction mixture to a pH of 5 to 7, treating the so-acidified reaction mixture with from about 1.0 to 2.0 mole equivalents of hydrazine, adding to said reaction mixture a catalyst selected from the group consisting of palladium on carbon, platinum on carbon and pre-reduced copper chromite, heating said mixture to refluxing temperatures, and recovering the desired 3,5-disubstituted pyrazole in good yield and purity.
2. A method according to Claim 1 wherein said catalytic dehydrogenation reaction is carried out in the presence of an inert gas.
3. A method according to Claim 1, which comprises:
reacting equimolar amounts of said ketone and said aldehyde in the presence of a C1-C4 alcohol and aqueous sodium hydrox-ide or potassium hydroxide at a temperature ranging from 20°C.
to 30°C., acidifying said reaction mixture with a mineral acid to pH ranging from 5 to 7, said acid being selected from the group consisting of hydrochloric acid, sulfuric acid and phosphoric acid, cooling said reaction mixture and treating said cooled mixture with from 1.0 to 2.0 mole equivalents of hydrazine hydrate while maintaining the temperature of said mixture between 20°C. and 30°C., distilling off a portion of the alcohol and adding to the remaining mixture an amount of an aromatic solvent, a cyclic ether, polar aprotic solvent, a chlorinated hydrocarbon, or a mixed xylene in an amount equivalent to about the alcohol removed, water washing the resulting mixture, admixing therewith a palladium on carbon catalyst, refluxing the resulting mixture, azeotropically distilling off water from the reaction mixture, hot filtering said mixture, cooling the filtrate from said filtration, and recovering the 3,5-disubstituted pyrazole from said filtrate.
reacting equimolar amounts of said ketone and said aldehyde in the presence of a C1-C4 alcohol and aqueous sodium hydrox-ide or potassium hydroxide at a temperature ranging from 20°C.
to 30°C., acidifying said reaction mixture with a mineral acid to pH ranging from 5 to 7, said acid being selected from the group consisting of hydrochloric acid, sulfuric acid and phosphoric acid, cooling said reaction mixture and treating said cooled mixture with from 1.0 to 2.0 mole equivalents of hydrazine hydrate while maintaining the temperature of said mixture between 20°C. and 30°C., distilling off a portion of the alcohol and adding to the remaining mixture an amount of an aromatic solvent, a cyclic ether, polar aprotic solvent, a chlorinated hydrocarbon, or a mixed xylene in an amount equivalent to about the alcohol removed, water washing the resulting mixture, admixing therewith a palladium on carbon catalyst, refluxing the resulting mixture, azeotropically distilling off water from the reaction mixture, hot filtering said mixture, cooling the filtrate from said filtration, and recovering the 3,5-disubstituted pyrazole from said filtrate.
4. A method according to Claim 1, wherein the catalyst employed is platinum on carbon, and the hydrazine reaction and catalytic dehydrogenation are conducted under a blanket of inert gas.
5. A method according to Claim 1, wherein the catalyst employed is prereduced copper chromite.
6. A method according to Claim 2, wherein the mineral acid is hydrochloric acid.
7. A method for the preparation of 3,5-diphenyl-pyrazole according to Claim 1 which comprises: reacting equimolar amounts of acetophenone and benzaldehyde in the presence of a base and a C1-C4 alcohol solvent, at a temper-ature between about 10°C. and 70°C., acidifying said reac-tion mixture to a pH of 7 or below with a mineral acid, treating the acidified reaction mixture with from about 1.0 to 1.5 mole equivalents of hydrazine under an inert blanket selected from the group consisting of nitrogen, argon, helium and carbon dioxide, while maintaining the temperature of the reaction mixture between about 10°C. and 70°C., separating from about 65% to 90% of said C1-C4 alcohol solvent from the reaction mixture and admixing with the remainder of the re-action mixture an amount of solvent approximately equivalent to the alcohol separated therefrom and selected from the group consisting of an aromatic solvent, a chlorinated hydro-carbon, and an ether, maintaining the said mixture under a blanket of inert gas selected from the group consisting of nitrogen, argon, helium and carbon dioxide, adding a catalyst selected from the group consisting of palladium on carbon or platinum on carbon to the reaction mixture, said mixture being brought to reflux temperatures, removing water azeo-tropically from said mixture, cooling said mixture to between 100°C. and 130°C., filtering the latter to remove catalyst therefrom, further cooling said filtrate to about 10°C., whereby the 3,5-diphenylpyrazole precipitates, and thereafter recovering said pyrazole from the reaction mixture.
8. A method for the preparation of 3,5-diphenyl-pyrazole according to Claim 1 which comprises: reacting equimolar amounts of acetophenone and benzaldehyde in the presence of methanol and an aqueous base selected from the group consisting of sodium hydroxide and potassium hydroxide at a temperature between 20°C. and 30°C., acidifying acid reaction mixture with a mineral acid to pH 5 to 7, said acid being selected from the group consisting of hydrochloric acid, sulfuric acid and phosphoric acid, cooling said reac-tion mixture, treating said cooled mixture with from 1 to 1.5 mole equivalents of hydrazine hydrate under an inert gas blanket selected from the group consisting of nitrogen, argon, helium and carbon dioxide, maintaining the temperature of said mixture between 20°C. and 30°C., distilling from 75% to 80% of the methanol and adding to the remaining mixture an amount of mixed xylenes equal to about the methanol removed, water washing the resulting mixture and admixing therewith under said inert gas blanket palladium on carbon catalyst, refluxing the resulting mixture at a temperature between 130°C.
and 150°C., azeotropically distilling off water from the re-action mixture, adding dimethylformamide to the resulting mixture, filtering said mixture to separate said catalyst therefrom, and recovering a filtrate containing 3,5-diphenyl-pyrazole.
and 150°C., azeotropically distilling off water from the re-action mixture, adding dimethylformamide to the resulting mixture, filtering said mixture to separate said catalyst therefrom, and recovering a filtrate containing 3,5-diphenyl-pyrazole.
9. A method according to Claim 6, wherein the catalyst employed is palladium on carbon.
10. A method according to Claim 6, wherein the catalyst employed is platinum on carbon.
11. A method according to Claim 7, wherein methanol is used as the solvent in the reaction of acetophenone and benzaldehyde and mixed xylenes are employed to effect the catalytic reduction.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US39828473A | 1973-09-17 | 1973-09-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1037048A true CA1037048A (en) | 1978-08-22 |
Family
ID=23574783
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA207,577A Expired CA1037048A (en) | 1973-09-17 | 1974-08-22 | Catalytic dehydrogenation process for the preparation of 3,5-disubstituted pyrazoles |
Country Status (20)
| Country | Link |
|---|---|
| JP (1) | JPS5855143B2 (en) |
| AR (1) | AR225264A1 (en) |
| AT (1) | AT339893B (en) |
| BE (1) | BE819948A (en) |
| BR (1) | BR7407147D0 (en) |
| CA (1) | CA1037048A (en) |
| CH (1) | CH596185A5 (en) |
| CS (1) | CS178177B2 (en) |
| DD (1) | DD115667A5 (en) |
| DE (1) | DE2441504A1 (en) |
| DK (1) | DK134643B (en) |
| ES (1) | ES430129A1 (en) |
| FR (1) | FR2243943B1 (en) |
| GB (1) | GB1477020A (en) |
| IL (1) | IL45399A (en) |
| IT (1) | IT1029578B (en) |
| NL (1) | NL168832C (en) |
| SE (1) | SE416648B (en) |
| SU (1) | SU645567A3 (en) |
| ZA (1) | ZA744908B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3910949A (en) * | 1974-12-09 | 1975-10-07 | American Cyanamid Co | Manufacture of 1,2-dimethyl-3,5-diphenylpyrazolium methylsulfate in a single reaction zone |
| DE3029160A1 (en) * | 1980-08-01 | 1982-03-04 | Basf Ag, 6700 Ludwigshafen | METHOD FOR PRODUCING PYRAZOLES |
| NZ216253A (en) * | 1985-05-27 | 1989-07-27 | Mitsui Toatsu Chemicals | N-(3-chloro-4-isopropylphenyl)-carboxamide derivatives and herbicidal compositions |
| DE69929345T2 (en) | 1998-08-07 | 2006-09-21 | Chiron Corp. (N.D.Ges.D. Staates Delaware), Emeryville | SUBSTITUTED ISOXAL DERIVATIVES AS ESTROGEN RECEPTOR MODULATORS |
| US6291505B1 (en) | 1998-08-07 | 2001-09-18 | Chiron Corporation | Estrogen receptor modulators |
| USRE39708E1 (en) | 1998-08-07 | 2007-06-26 | Chiron Corporation | Estrogen receptor modulators |
| AU2005287170B2 (en) * | 2004-09-17 | 2012-03-29 | Exelixis, Inc | Pyrazole kinase modulators and methods of use |
| NZ588442A (en) * | 2008-06-09 | 2013-01-25 | Univ Muenchen L Maximilians | Pyrazole, isoxazole and imidazole derivatives for treating diseases linked to protein aggregation and neurodegenerative diseases |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2260485C2 (en) * | 1971-12-17 | 1983-12-29 | American Cyanamid Co., Wayne, N.J. | 1,2-dialkyl-3,5-diphenylpyrazolium salts and herbicidal agents containing them |
| DE3209148A1 (en) * | 1982-03-13 | 1983-09-22 | Basf Ag, 6700 Ludwigshafen | METHOD FOR PRODUCING PYRAZOLES BY CATALYTIC DEHYDRATION OF PYRAZOLINES |
-
1974
- 1974-07-31 ZA ZA00744908A patent/ZA744908B/en unknown
- 1974-08-04 IL IL45399A patent/IL45399A/en unknown
- 1974-08-15 GB GB3603874A patent/GB1477020A/en not_active Expired
- 1974-08-22 CA CA207,577A patent/CA1037048A/en not_active Expired
- 1974-08-22 AR AR255275A patent/AR225264A1/en active
- 1974-08-28 BR BR7147/74A patent/BR7407147D0/en unknown
- 1974-08-30 DE DE2441504A patent/DE2441504A1/en active Granted
- 1974-09-06 IT IT52913/74A patent/IT1029578B/en active
- 1974-09-11 DD DD181031A patent/DD115667A5/xx unknown
- 1974-09-11 CH CH1237174A patent/CH596185A5/xx not_active IP Right Cessation
- 1974-09-12 NL NLAANVRAGE7412119,A patent/NL168832C/en not_active IP Right Cessation
- 1974-09-12 AT AT738174A patent/AT339893B/en not_active IP Right Cessation
- 1974-09-16 DK DK487274AA patent/DK134643B/en not_active IP Right Cessation
- 1974-09-16 SU SU742059902A patent/SU645567A3/en active
- 1974-09-16 FR FR7431248A patent/FR2243943B1/fr not_active Expired
- 1974-09-16 SE SE7411650A patent/SE416648B/en not_active IP Right Cessation
- 1974-09-16 CS CS6341A patent/CS178177B2/cs unknown
- 1974-09-16 BE BE148556A patent/BE819948A/en not_active IP Right Cessation
- 1974-09-17 ES ES430129A patent/ES430129A1/en not_active Expired
- 1974-09-17 JP JP49107068A patent/JPS5855143B2/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| JPS5855143B2 (en) | 1983-12-08 |
| NL7412119A (en) | 1975-03-19 |
| DE2441504C2 (en) | 1987-11-26 |
| DD115667A5 (en) | 1975-10-12 |
| AT339893B (en) | 1977-11-10 |
| AR225264A1 (en) | 1982-03-15 |
| GB1477020A (en) | 1977-06-22 |
| NL168832C (en) | 1982-05-17 |
| IT1029578B (en) | 1979-03-20 |
| CS178177B2 (en) | 1977-08-31 |
| ZA744908B (en) | 1975-08-27 |
| BE819948A (en) | 1975-03-17 |
| DE2441504A1 (en) | 1975-03-20 |
| IL45399A0 (en) | 1974-11-29 |
| CH596185A5 (en) | 1978-03-15 |
| DK134643C (en) | 1977-05-16 |
| DK487274A (en) | 1975-05-12 |
| IL45399A (en) | 1979-01-31 |
| SE7411650L (en) | 1975-03-18 |
| FR2243943A1 (en) | 1975-04-11 |
| FR2243943B1 (en) | 1986-07-04 |
| AU7202874A (en) | 1976-03-11 |
| DK134643B (en) | 1976-12-13 |
| NL168832B (en) | 1981-12-16 |
| JPS5058068A (en) | 1975-05-20 |
| BR7407147D0 (en) | 1975-07-29 |
| SE416648B (en) | 1981-01-26 |
| ATA738174A (en) | 1977-03-15 |
| SU645567A3 (en) | 1979-01-30 |
| ES430129A1 (en) | 1977-01-16 |
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