Note: Descriptions are shown in the official language in which they were submitted.
~ 35~D 0.~. C050/03~4
Preparation of pyrazoles
me present invention relates to a novel process
for the preparation of pyrazoles by reacting 1,3-dicar-
bonyl compounds with hydrazines and a less than equiva-
lent amount of acid at a pX of from 0 to 6.9.
Rodd, Chemistry of Carbon Compounds, volume IVa
(Elsevier, N.Y., 1957), pages 246 - 249, discloses
numerous syntheses of pyrazoles, for example by reacting
hydrazines with 1,3-dicarbonyl compounds, by dehydration
of hydrazones of ~-keto-esters, by cyclization of hydra-
zo~es of a-cyano-ketones, by reaction of aldehyde-
phenylhydrazones with ~-keto-esters in the presence of
zinc chloride, by condensation of a-halohydrazones with
sodium-keto compounds or by reaction
of diazo compounds with acetylene derivatives. The
more important methods of synthesis entail the reaction
of derivatives of 1,3-dicarbonyl compounds with hydra-
zine or hydrazine derivatives in an acid aqueous solution
or with salts of hydrazine orhydrazine derivatives, togive
diluteaqueous solutionsofpyrazole salts, For example
J. Amer. Chem. Soc., 71 (1949), 3,997, describes the
stoichiometric reaction of 1,1,3,3-tetraethoxypropane
with hydrazine dihydrochloride in a water/ethanol mixture.
The solution is then e~aporated to dryness, the residue
is taken up in water and the pyrazole is liberated from
its salt in the solution by means of sodium bicarbonate.
The mixture is filtered, the filter residue is thoroughly
washed with ether and the ether filtrate is used to
extract the aqueous filtrate.
3~HD
2 0. .0~50/0
Since these syntheses start from salts ~ hydra-
zine (or of its derivatives) in solution, it is unavoid-
able that stoichiometric amounts of waste salts should
be produced after using, for example, inorganic bases.
When dumped on an industrial scale, these salts cause
substantial effluent problems and problems of protecting
the environment. For example, using the above method
(J. Amer. Chem. Soc., loc. cit.) more than 2 kg of
sodium chloride are formed per kg of pyrazole produced.
We have found that pyrazoles of the formula
'' R~l
R
~.
; where the individual radicals Rl, R2 and R3 may be
identical or different and each is hydrogen or an
aliphatic, araliphatic or aromatic radical, R2 may also
be halogen, -CN or -o-R4, R3 may also be -0 , and R4
-C-R4
is an aliphatic, araliphatic or aromatic radical, are
obtained in an advantageous manner by reaction of a
1,3-dicarbonyl compound with a hydrazine in ~he presence
of water and of an acid, if a 1,3-dicarbonyl compound
of the formula
II
o R20
R -C-C_c_Rl
where Rl and R2 have the above meanings, is reacted with
i~41390
- 3 - o.Z. 0050/033~94
a hydrazine of the formula
R3-HN-NH2 III
where R3has theabove meanings. in the presence of less
than 2 equivalents of acid per mole of hydrazine III at
from -10 to +100C, the pH of the reaction mixture
during the reaction being from 0 to 6.9.
Further, we have found that the process accord-
ing to the i~vention may be carried out advantageously
if the proportion of the pyrazole I present in the reac-
tion mixture in the form of the pyrazole salt is reacted
with additional hydrazine III to give the free pyrazole I
Compared to the prior art, the process according
to the in~ention surprisingly gives pyrazoles by a
simpler and more economical method, and in better yield
and greater purity. Substantial amounts of acid,
and hence expensive neutralization and effluent purifi-
cation operations, are saved; The process causes less
pollution of the environment. A11 these advantageous
results are surprising in view of the prior art. In
the light of the conventional processes, lower conver-
sions and yields and the formation of heterogeneous
mixtures of starting base and end product base, and of
their salts, were to be expected.
The starting material II is reacted with the
starting material III in stoichiometric amounts, or
using an excess of one component relative to the other,
preferably using from 0.1 to 1.5, especially from 0.9
to 1.1, moles of starting material III per mole of
starting material II. Preferred starting materials II
3~KD
- 4 - 0.~.. 005~033~94
and III and accordingly preferred end products I are
those where the individual radicals Rl, R2 and R3 may
be identical or different and each is hydrogen, alkyl
of 1 to 18, preferably of 1 to 6, carbon atoms, araIkyl
or alkylaryl of 7 to 12 carbon atoms, phenyl or naphthyl,
R2 may also be bromine or chlorine, -CN or -o-R4 and R3
may also be -0 4, R being alkyl of 1 to 18, preferably
: 1 to 6, carbon atoms, aralkyl or alkylaryl of 7 to 12
carbon atoms, phenyl or naphthyl. The said radicals
may in addition be substituted by groups which are
inert under the reaction conditions, for example alkyl
of 1 to 3 carbon atoms or cyano.
Instead of 1,3-dicarbonyl compounds II, materials
which form these compounds under the reaction conditions
are as a rule employed. In the main, bis-acetals,
mono-acetals, bis-acylals and mono-acylals are.used.
Ad~antageous compounds to employ are those of the
formula
6 , R, R 5 IV
H H X
R5
or R - C - C - C - R5
H
R2 R~
or R1-C = C - C - R5 VI
H H
11~1390
_ 5 _ o.~. 0050/03389
where the individual radicals R5 and R6 may be identical
or different and each is -oR4 or -o-C-R4, the two
radicals R5 may also together be oxo, R5 may also be
halogen, advantageously chlorine, and Rl, R2 and R4
have the above general and preferred meanings.
Where 1,1,3,3-tetramethoxypropane and hydrazine
are used, the reaction can be represented by the
following equation:
OCH3 OCX3
CH30-C-CX2-C-OC~3 + H~ ~H2 > ~ + 4CH30H .
H H
- Examples of suitable starting materials II are
1,1,3,3-tetramethoxy-, -tetraethoxy-, -tetrapropoxy-,
-tetraisopropoxy-, -tetrabutyoxy-,-tetraisobutoxy-,
-tetra-sec.-butoxy- and -tetra-tert.-butoxy-propanes
which are unsubstituted or are a-substituted by methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl,
tert.-butyl, benzyl, phenyl, chloro, cyano, methoxy,
ethoxy, propoxy, isopropoxy, butoxy, sec.-butoxy,
isobutoxy, tert.-butoxy, benzoxy or phenoxy, 3,3-
dimethoxy-, 3,3-diethoxy-, 3,3-dipropoxy-, 3,3-diiso-
propoxy-, ~,3-dibutoxy-, 3,3-diisobutoxy-, 3,3-di-tert.-
butoxy and 3,3-di-sec.-but~xy-propionaldehydes which are
unsubstituted or a-substituted as above, and 1,1-
dimethoxy-, l,l-diethoxy-, l,1-dipropoxy-, 1,1-diiso-
propoxy-, 1 t l-dibutoxy-, l,l-diisobutoxy-, l,l-di-sec.-
~ 3~KD
_ ~ _ 0.~. 0050~033Q94
butoxy- andl,l-di-tert~ -butoxypropanals which
are unsubstituted or -substituted as above~homologous
~-oxo-butanals, ~-oxo-pentanals, ~-oxo-hexanals, ~-oxo-
heptanals and ~-oxo-octanals which are unsubstituted or
substituted as abo~e in the a-position; pentane-2,4-
diones, hexane-2,4-diones, heptane-2,4-diones, oetane-
2,4-diones, heptane-3,5-diones and octane-3,5-diones
which are unsubstituted, or substituted as above, in the
-position relative to both carbonyl groups; correspon-
ding l,l-acetalized ~,~-unsaturated butenals, pentenals
and hexenals which are unsubstituted or substituted as
above in the a-positiOn; l~l-acetalized propargyl-
Pldehydes and homologous ,~-unsaturated butynals,
pentynals and hexynals.
Preferred compounds to use are 1,1,3,3-tetra-
methoxypropane, 1,1,3,3-tetraethoxypropane, 1,1,3,3-
tetraisobutoxypropane, 1,1,3,3-tetraisopropoxypropane,
1,1,3,3-tetrabutoxypropane and 1,1,3,3-tetrapropoxy-
propane.
Examples of suitable hydrazines III are hydra-
zine, which is unsubstituted or substituted by methyl,
ethyl, propyl, isopropyl, butyl, sec.-butyl, tert.-
butyl, isobutyl, benzyl, phenyl, acetyl, benzoyl or
phenylacetyl . Instead of the hydrazines III, com-
pound~s which form these hydrazines under the reaction
11~1390
- , - 0.~. CO~0/~33R~
conditions may also be used, for example the hydrazine
hydrates, salts of the hydrazines, such as the sulfates
or disulfonates, eg. the di-benzenesulfonates; and
hydrazones, eg. with formaldehyde or acetaldehyde,
together with amines, eg. ethylamine.Where salts are
used, the total amount of free acid and acid bonded
to hydrazine is always less than 2 equivalents per mole
of hydrazine.
me reaction is carried out at from -10 to +100C,
preferably from O to 100C, especially from 30 to 70C,
under atmospheric or superatmospheric pressure, contin-
uously or batchwise. Organic solvents which are inert
under the reaction conditions may or may not be added.
Examples of suitable solvents are aromatic hydrocarbons,
eg. toluene, ethylbenzene, o-, m- or p-xylene, isopropyl-
benzene and methylnaphthalene; halohydrocarbons, especi-
ally chlorohydrocarbons, eg. tetrachloroethylene,
1,1,2,2- and 1,1,1,2-tetrachloroethane, amyl chloride,
dichloropropane, methylene chloride, dichlorobutane,
carbon tetrachloride, 1,1,1- and 1,1,2-trichloroethane,
trichloroethylene, pentachloroethane, 1,2-dichloroethane,
l,l-dichloroethane, n-propyl chloride, 1,2-cis-dichloro-
ethylene, n-butyl chloride, 2-, 3- and iso-butyl chloride,
chlorobenzene, o-, p- and m-dichlorobenzene, o-, m- and
p-chlorotoluene and 1,2,4-trichlorobenzene; ethers, eg.
ethyl propyl ether, methyl tert.-butyl ether, n-butyl
ethyl ether, di-n-butyl ether, diisobutyl ether, diiso-
amyl ether, diisopropyl ether, cyclohexyl methyl ether,
li ~l390
- 8 - o.Z. 00~0~0338
diethyl ether, ethylene glycol dimethyl ether, tetra-
hydrofuran and dioxane; alkanols and cycloaIkanols, eg.
ethanol, methanol, n-butanol, isobutanol, tert.-butanol,
glycol, n-propanol, isopropanol, amyl alcohol, cyclo-
hexanol, 2-methyl-pentan-4-ol, ethylene glycol monoethyl
ether, 2-ethylhexanol and methylglycol, those of 1 to 4
carbon atoms being preferred; aliphatic and cyclo-
aliphatic hydrocarbons, eg. heptane, pinane, nonane,
gasoline fractions boiling within the range from 70 to
190C, cyclohexane, methylcyclohexane, decalin, petroleum
ether, hexane, naphtha, 2,2,4-trimethylpentane, 2,2,3-
trimethylpentane, 2,3,3-trimethylpentane and octane;
and mixtures of the above. Advantageously, the amount
of solvent used is from 400 to 10,000 percent by weight,
preferably from 100 to 500 percent by weight, based on
starting material II.
Water is used in every case, advantageously in
an amount of from 1 to 70, more especially from 1 to 10,
moles per mole of hydrazine III. The water is advan-
tageously added to the starting mixture together withanother reactant, for example together with the acid
and/or together with the starting material III.
The reaction is carried out in the presence
of less than 2 equivalents of acid, and advantageously
with from 0.05 to 1.9, especially from 0.25 to 1.25,
equivalents of acid per mole of starting material III.
Inorganic or organic acids may be used. Instead of
monobasic acids, equivalent amounts of polybasic acids
may also be employed. Examples of suitable acids are
1~1390
_ 9 ~ ,. 005c/03~a4
the following: inorganic acids, eg. hydrochloric acid,
hydrobromic acid, sulfuric acid and phosphoric acid;
sulfonic acids, eg. benzenesulfonic acid and p-toluene-
sulfonic acid; boron-containing acids, eg. boric acid
and fluoboric acid; aliphatic carboxylic acids, eg.
chloroacetic acid, dichloroacetic acid, trichloroacetic
acid, ~xalic acid, formic acid, acetic acid, propionic
acid, butyric acid, isobutyric acid, glycolic acid and
a- and ~-chloropropionic acid; and mixtures of the above.
The acids may be used in a concentrated form, as mixtures
with one another and/or as mixtures with a solvent,
especially water. The preferred acid is hydrochloric
acid. The reaction is carried out at a pH of from
0 to 6.9, preferably from 0.5 to 4, especially from 0.9
to 2.5.
The reaction may be carried out as follows:
a mixture of hydrazine III, acid and water is brought
to the reaction pH and additional starting materials III
and II are then added simultaneously, with or without
water and/or organic solvent, at a rate such that the
reaction pH is always maintained. Advantageously,
the reactants are added at from -lO to +60C over a
period of from 5 to 30 minutes. The total reaction
time is advantageously from 0.1 to 12 hours. It has
proved to be an important advantage of the novel process
that the total amount of acid which need be added is
very small relative to the hydrazine derivative.
The end prod~ct can be isolated from the
~141390
- 10 - o,~.. 00~0~033~a4
reaction mixture in a conventional manner, for example
by neutralizing and extracting the mixture and distilling
the extract. In batchwise operation, neutralization
may for example be ef~ected by an inorganic base, in
which case, according to the invention, the amount of
salt formed as a by-product is only that which corres-
ponds to the small amount of acid employed. However,
particularly in continuous operation, the pyrazoles I
are liberated, according to the invention, by adding the
corresponding hydraz~ne III to thé reaction mixture,
the pH advantageously being brought to 6 - 10 before
carrying out the extraction. As is illustrated, for
the example of pyrazole, by the equation below, this
results in the re-formation of re-usable hydrazine salt
in the solution.
N ~ HCl + H ~ -NH2 x H20 _~ ~ +~ ~ -NH2 x XCl + H20
~ H
It is advantageous that acid losses only occur to the
extent of acid being lost from the aqueous phase during
distillation and extraction processes. The liberation
of the end product I by means o~ additional hydrazine
is advantageously carried out at 0 - 40C. Using the
above method, the resulting hydrazine salt solution can
be re-used in reactions which can in principle be
repeated as often as desired, and this is a substantial
and surprising advantage of the novel process.
The pyrazoles I obtainable by the process of the
11 ~139H3
- 11 - o.Z. 0050/03389
invention are valuable starting materials for the prepar-
ation of dyes, crop protection agents and drugs. With
regard to their use, reference may be made to the publi-
cations mentioned earlier.
In the Examples which follow, parts are by weight
and bear the same relation to parts by volume as that of
the kilogram to the liter.
EX~MPLE 1 '
320 parts of water and 20 parts (0.4 mole) of
hydrazine hydrate are introduced into a stirred apparatus
and brought to pH 1, at 40C, by adding 59 parts of
aqueous 36 percent strength by weight hydrochloric acid
(O.5 mole). The followingareaddedsimultaneouslyin ~rti~s
o~er2~hours,from threestock vessels,soastomaintain apH
of 2 -3: 380 parts(7.6 moles) of hydrazine hydrate, ~4
parts of aqueous 36 percent strength by weight hydro-
chloric acid (3.54 moles) and 1,312 parts (8 moles) of
3~3-tetramethoxypropane. The mixture assumes a
temperature of 43 - 55C, without cooling. The speed
of rotation of the l,1,3,3-tetramethoxypropane is kept
constant at 540 parts by volume per hour whilst that of
the hydrazine is set to 153 parts per hour; the pH is
regulated by the addition of the hydrochloric acid,
After finally stirring for 7 hours, the mixture is
brought to pH 8 by adding 320 parts (4 moles) of NaOH,
and 1,553 parts of a methanol/water mixture and then
1141390
- 12 - 0.~. 00~0/033~94
distilled off in 2~ hours at 20 mbar/50C. The residue
is stirred with 2,000 parts by volume of methylene chlor-
ide and filtered- The filter residue contains 250 parts
of NaC~ whilst distillation of the filtrate gives 445
parts (82 % of theory) of pyrazole of boiling point 60 -
70C/0.3 mbar.
EXAMPLE 2
a) 12.9 parts (0.258 mole) of hydrazine hydrate
are introduced into a stirred apparatus equipped with a
pH electrode, and are neutralized with 50.6 parts of
aqueous hydrochloric acid (0.506 mole), whilst cooling.
At this stage hydrazine hydrochloride precipitates.
1,1,3,3-Tetramethoxypropane and additional hydrazine
hydrate are then added simultaneously at 45 - 50C,
at a rate such that a pH of 1 - 2 is maintained, which
requires the addition of 82 parts (0.5 mole) of 1,1,3,3-
tetramethoxypropane and 15.5 parts (0.31 mole) of hydra-
zine hydrate over 20 minutes. After completion of
the addition, the pH is 1. The mixture is then stirred
for 2 hours at 22CC.
b) 120 parts by volume (= 3/4)of this solution are
thenbrought to pH 6.8 - 7.2 with 20.6 parts by volume
(0.426 mole) of hydrazine hydrate, and the mixture is
then extracted with 2 x 200 parts by volume of CH2C12~
orming a binding system of hydrazine hydrate phase and
extract. Distillation of
the extract gives 23.2 parts of pyrazole (85 % of theory)
of ooiling point 60 - 70C/0.1 mbar.
c, The last quarter, namely 40 parts by volume, of
3~3
- 13 - 0.~ tO~
the reaction solution obtained in Example 2a) are then
taken - this solution being at pH 1 - and 61.5 parts
(0.375 mole) of 1,1,3,3-tetramethoxypropane,and the
aqueous hydrazine hydrate phase (pH 6.9 - 7.2) extracted
in b), are added over 20 minutes, similarly to Example
2a. The pH again assumes a value of 1 - 2. After
a further 2 hours, the mixture is worked up in the same
m~nner as in Example 2b). Distillation gives 21.45
parts (0.36 mole) of pyrazole (corresponding to 84 %
yield), of boiling point 60 - 70C/0.1 mbar.
d) Procedure c) is repeated for 10 further reac-
- tions. Even in the lOth case, the pH of the reaction
mixture is again 1.6 - 1.7 and the same results as in
Example 2c) are obtained.
