Note: Descriptions are shown in the official language in which they were submitted.
"~ ~ 1 6~323
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8-13182/TEL 225/1-3/~
Process for the preparation of pyrazolidin-3-ones
-
The present invention relates to a process for the
preparation of pyrazolidin-3-ones.
A process for the preparation of 1-phenyl-4,4-di-
hydroxymethyl-pyrazolidin-3-one, 1-p-tolyl-4,4-dihydroxy-
methyl-pyrazolidin-3-one and 1-phenyl-4-methyl-4-hydroxy-
methyl-pyrazolidin-3-one is already known from British
Patent Specification 1,157,617. According to this,
a ~:-hydroxy-carboxylic acid ester is reacted with an aryl-
hydrazine in the presence of an alcoholate to give the cor-
responding arylhydrazide which is then cyclised, to the
pyrazolidin-3-one, by heating for example in¦the
presence of anhydrous p-toluenesulf onic acid .
This process is not yet fully satisfactory in every
respect, since it must be taken through several stages and
requires relatively long reaction times.
It is therefore the object of -the present invention
to~provlde a process for the preparation of pyrazolidin-3-
ones, which process leads to the desired product in a smal-
ler number of intermediate stages, in shorter reaction times
and in higher yields.
It has now been found that the object of the inven-
tion can be achieved by direct formation of the hydrazide
from the carboxylic acid component and hydrazine component
and by subsequent cyclisation, in a single-stage or two-
stage reaction.
The presence of an acid catalyst is necessary for
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cyclising the hydrazide. In some cases, this catalyst is
already present in the reaction mixture during the formation
of the hydrazide.
The present invention thus relates to a process for
the preparation of pyrazolidln-3-ones of the formula
13 ~0
(1) 2 i ~ H
R `
in which Rl is substituted or unsubstituted phenyl, R2 is
alkyl or hydroxyalkyl each having 1 to 4 carbon atoms and
R3 is hydroxyalkyl having 1 to 4 carbon atoms, which com-
prises reacting a ~-hydroxypropionic acid of the formula
(2) 12
R3
in which R2 and R3 are as defined above, with a hydrazine
of the formula~
(3) ~ NH-NH2
R4
in which R4 is hydrogen, alkyl or alkoxy each having 1 to
4 carbon atoms, hydroxyl or halogen, to give a ~-hydroxy-
propionic acid hydrazide and cyclising the latter, if option-
ally in the same reaction mixture, in the presence of an
acid catalyst.
In a preferred embodiment of the process according
to the invention, a ~-hydroxypropionic acid of the formula
(2) is reacted with a hydrazine of the formula (3) to give
a ~-hydroxypropionic acid hydrazide which is cyclised in the
same reaction mixture in the presence of an acid catalyst.
According to a particularly preferred variant of the
process according to the invention, even the formation of
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the hydrazide is also carried out in the presence of an acid
catalyst.
The present invention also relates to the pyrazoli-
din-3-ones prepared by the process according to the inven-
tion.
The present invention also relates to the use of the
pyrazolidin-3-ones, prepared according to the invention, in
photographic developer solutions.
The substituent Rl in the formula (l) is substituted
or unsubstituted phenyl of the formula
R4.=7
In this formula, R4 is hydrogen, alkyl or alkoxy each having
l to 4 carbon atoms, such as methyl, propyl, i-propyl or
butyl, or methoxy or butoxy. Methyl and methoxy are pre-
ferred. R4 can also be hydroxyl or halogen. The
preferred halogen is chlorine. The preferred meaning of
Rl is phenyl.
R2 is alkyl or hydroxyalkyl each having l to 4 car-
bon atoms, such as methyl, ethyl~ hydroxymethyl and l- or
2-hydroxyethyl. Methyl and hydroxymethyl are particularly
suitable.
R3 is hydroxyalkyl having l to 4 carbon atoms.
Examples are hydroxymethyl, l- or 2-hydroxyethyl and l- or
4-hydroxybutyl. Preferably, R3 is hydroxymethyl~
Preferably, in the process according to the inven-
tion, a ~-hydroxypropionic acid of the formula
(4) 15
HO--CH2~ COOH
~ R6
in which R5 is methyl, ethyl,thydroxymethyl or l- or 2-hy-
droxyethyl and R6 is hydroxymethyl or l- or 2-hydroxyethyl,
in particular of the formula
(5) R7
HO--CH2~ OOH
,, Ci~2-oH
1 ~ ~532~
in which R7 is methyl or hydroxymethyl, is reacted with a
phenylhydrazine of the formula
(6) ~ NH-NH~
R8
in which R8 is hydrogen, methyl, methoxy, hydroxyl or
chlorineO
Phenylhydrazines which are particularly suitable
for the process according to the invention are of the Por-
mula
(7) ~; / 2
, Rg
in which Rg is hydrogen, methyl or methoxy.
Preferably, in the process according to the inven-
tion, a ~-hydroxypropionic acid of the formula
CH3
(8) Ho_cH2-~-cOOH
CH20H
and phenylhydrazine are used for the preparation of the
hydrazide of the formula
CH3
( 9 ) Ho-cH2-¢-co-NH-NH- ~
and the latter is converted in the presence of an acid cata-
lyst into 1-phenyl-4-methyl-4-hydroxymethyl-pyrazolidin-3-
one.
In a particularly preferred process, both the for-
mation of the hydrazide of the formula (9) and the cyclisa-
tion thereof to give 1-phenyl-4-methyl-4-hydroxymethyl-pyra-
zolidin-3-one are carried out in the presence of an acid
catalyst.
The process according to the invention can be
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carried out as a so-called one-vessel reaction, viz. the
hydrazide is not isolated before the cyclisation. As a
rule, the reactions are carried out at elevated temperatures,
for example at 100 to 1~0C. Temperature ranges of 110
to 140C, in particular 120 to 140C, are preferred. The
range from 125 to 135C is particularly suitable. The
molar ratios of the ~-hydroxypropionic acid to the hydra-
zine component can be selected such that either the acid
component or the hydrazine component is present in excess.
As a rule, the acid component is used in an excess of not
more than 100%, relative to the hydrazine component. On
the other hand, it is possible, however, to work with a very
large excess of hydrazine component. For example, good
yields of pyrazolidin-3-ones are obtained in this way, if
the hydrazine component is used as the solvent.; More suit-
able ratios of acid component to hydrazine component are,
however, in the range of about 1:5. Ratios from 1:1 to
1:3 are of interest. Preferably, a ratio from 1:2 to
1:3, in particular a ratio from 1:1.5 to 1:2.5, is selected.
If the components are employed in a molar ratio of
1.5:1 to 2:1, the excess carboxylic acid can fulfil the
function of the acid catalyst, by effecting the cyclisation
of the hydrazine to give the pyrazolidin-3-one. If, how-
ever, the starting compounds are present in molar ratios of
1 to 1:5, the presence of an acid catalyst is necessary
for the cyclisation and, in some cases, is advantageous for
the formation of the hydrazide. Examples of such a cata-
lys-t are inorganic or organic acids, such as aliphatic or
aromatic carboxylic or sulfonic acids. Hydrogen chloride
or hydrogen bromide, or-tho-phosphoric acid, polyphosphoric
acid, phosphorus pentoxide, pyrophosphoric acid or an acid
salt of ortho-phosphoric acid, and also benzenesulfonic acid,
p-toluenesulfonic acid, methanesulfonic acid, carbon dioxide,
sulfur dioxide or sulfuric acid are preferred. Hydrogen
chloride, ortho-phosphoric acid,methanesuIfonic acid and
and sulfuric acid are particuIarly suitable. Ortho-phos-
phoric acid is a very suitable catalyst.
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It is also possible in the process according to the
invention to use a mixture of such catalysts. Moreover,
in cases where the catalyst is present in the reaction mix-
ture from the start, it can be advantageous to replace the
originally used catalyst by a more strongly acid catalyst
at a certain point in time during the process, for example
after the major quantity of hydrazide has been formed.
According to a further variant of the process
according to the invention~the cyclisation of the hydrazide
by means of an acid is effected in the melt.
The hydrazide can also be formed by fusing the acid
component and the hydrazine component together. Prefer-
ably, however, this reaction is carried out in a concentra-
ted solution. Examples of suitable solvents are xylene,
toluene~ chlorobenzene, 1,2-dichlorobenzene and ethylben-
zene.
Advantageously, the water formed in the cyclisation
is continuously removed from the reaction mixture. For
example, solvents or solvent mixtures, which form azeotropic
mixtures with water and the boiling points of which are be-
low the reaction temperature, are suitable for this purpose.
The abovementioned solvents are suitable examples.
The water can also be removed from the reaction mix-
ture by applying a vacuum. This method is suitable es-
pecially when the reactions are carried out in the melt,
without a solvent.
The process according to the invention is explained
by reference to the examples which follow.
A. Preparation of the phenylhydrazide of 2,2-dihydroxymethyl-
propionic acid.
. . .
Example 1 134.14 g (1 mol) of 2,2 ~ dihydroxymethylpro-
pionic acid and 216.28 g (2 mols) of phenylhydrazine are
introduced into a three-necked sulfonation flask of 1.5 l
capacity, equipped with a stirrer, thermometer and a 20 cm
~igreux column with a distillation apparatus connected
thereto. With good stirring, the mixture is heated to an
internal temperature of 130C. As soon as this has been
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reached,a vacuum of 50 to 70 mm Hg is applied to the solu-
tion which now has a yellow-orange colour, so that the water
formed during the reaction is removed as rapidly as pos-
sible. The reaction is allowed to proceed for 4 hours at
130C, and the distillation should be controlled in such a
way that, during this time, all the water and as little
phenylhydrazine as possible are distilled off. Towards
the end of the reaction the vacuum and the temperature are
increased, in order to remove the excess phenylhydrazine
and other by-products, which have formed, from the reaction
mixture. The batch is allowed to cool to 120C, and
150 ml of methyl "Cellosolve"* and 750 ml of xylene are added,
during which the temperature should not fall below 100C.
At about 90C, the reaction product starts to crystallise
out. The mixture is allowed to cool slowly to room tem-
perature, the crystalline reaction mass is filtered off and
the yellowish residue is washed with about 200 ml of xylene
and then with 100 ml of petroleum ether (boiling point
60 - 90C). After drying in vacuo at 60C, 179 g of the
white, crystalline compound of the formula (9) having a
melting point of 127 to 130C are obtained. In addition
to a main spot, the thin-layer chromatogram (CHC13: CH30H
= 85 : 15) shows only a trace of the dihydroxymethylpropio-
niC acid starting material.
After crystallisation from water or acetone, the
melting point of the 2,2-dihydroxymethylpropionic acid
phenylhydrazide rises to 140 to 142C.
Example 2. In the same apparatus, the same procedure as in
Example 1 is followed, except that only 119 g of phenyl-
hydrazine are employed instead of 216 g; this gives 171 g
of the compound of the formula (9) in the form of a light
beige product having a melting point of 113 to 117C,
or of 140 to 142C after crystallisation from
water.
Example 3: 134 g of 2,2-dihydroxymethylpropionic acid and
540 g of phenylhydrazine are introduced into the apparatus
described in Example 1. With stirring, the mixture is
* Trademark for ethylen~ glycol monomethyl ether
(or 2-methoxyethanol).
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heated for 4 hours at 130C, water being removed from the
reaction medium in the manner described in Example 1. At
the end of the reaction, the excess phenylhydrazine is re-
moved by distillation. After the addition of 400 ml of
xylene and 20 ml of ethanol at 120 to 130C, the compound
of the formula (9) starts to crystallise. After cooling
to room temperature, filtration and washing of the residue
with a little xylene and 1,2-dichloroethane, the product is
dried at 60C in vacuo. This gives 217.5 g of white
crystals having a melting point of 127 to 133C. After
recrystallisation from water or acetone, the melting point
of the product is 139 to 141C.
Example 4 67 g of 2,2-dihydroxymethylpropionic acid and
65 g of phenylhydrazine are introduced into a three-necked
sulfonation flask of 350 ml capacity, equipped with a stir-
rer, thermometer, gas inlet tube and a water separator with
a reflux condenser. With stirring, the mixture is heated
to an internal temperature of 130~C, the water formed being
removed from the reaction medium by passing through a
vigorous stream of nitrogen. After a reaction time of
4 hours at 130C, 30 ml of ethanol and 200 ml of xylene are
added at about 80C, and the mixture is allowed to cool
slowly to room temperature. After filtration, the com-
pound of the formula (9) is washed with petroleum ether and
dried in vacuo at 60C. This gives 97 g of a light beige
product having a melting point of 110 to 116C, or 138 to
141C after crystallisation from water or acetone.
B. Preparation_of 1-phenyl-4-methyl-4-hydroxymethyl-pyra-
zolidin-3-one.
Example 5: 77.8 g (0.35 mol) of the phenylhydrazide of the
formula (9) as well as 350 ml of xylene and 350 ml of
methyl "Cellosolve" are introduced into a three-necked sulfona-
tion fla~k of 750 ml capacity, equipped with a stirrer,
thermometer and distillation apparatus with a water separa-
tor. With good stirring, gaseous hydrogen chloride is
passed through and the mixture is heated. At 115C, a
mixture of xylene, methyl "Cellosolve" and water distils over,
3 2 3
and this is removed. The distillation temperature rises
slowly to 128C. After two hours, the reaction has ended.
The major part of the xylene is distilled off. 250 ml of
T,~ater are added to the residue, and the remaining xylene is
distilled off azeotropically. The remaining clear solu-
tion is cooled down slowly, with stirring. The crystal-
line reaction mass is filtered off and briefly washed with
cold water. This gives 58.5 g of a light yellow crystal
powder of the formula
(101) ~ ~H3 ~0
HOCH/~ ~ H
having a melting point of 119 to 120C. After recrystal-
lisation from water, the 4-hydroxymethyl-4-methyl-1-phenyl-
pyrazolidin-3-one melts at 123 to 124C. The same results
are obtained when, in place of gaseous HCl, the following
acid catalysts are employed: H2S04, gaseous S02 or C02, p-
toluenesulfonic acid, methanesulfonic acid and benzenesul-
fonic acid, or mixtures of these acids.
Example_6: 3,000 ml of xylene are initially introduced
into a four-necked round-bottomed flask of 5 l capacity,
equipped with a thermometer, stirrer, filling branch and
reflux condenser with a water separator. With stirring,
108 g (l.l mol) of crystallised ortho-phosphoric acid are
introduced, the mixture is heated to 100C by means of an
oil bath, and 259.5 g (236 ml, 2.4 mols) of phenylhydrazine
are added, the temperature rising to 115 to
120C, and a light yellow suspension being formed. Subse-
quently, 80.5 g (0.6 mol) of 2,2 bishydroxymethylpropionic
acid are introduced. The mixture is heated to 135C, and
the water being formed is azeotropically separated off in
the water separator. After a reaction time of 30 minutes,
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another 80.5 ~ (0.6 mol) of bishydroxymethylpropionic acid
are added, and heating under reflux is continued for21hours.
(The quantity of water separated off is about 40 ml).
Subsequently, 10 g of kieselguhr and 4 g of active charcoal
are added to the reaction mixture which is filtered hot on
a porcelain suction filter. After cooling to 0C, 145 g
of pale pink-coloured 1-phenyl-4-methyl-4-hydroxymethyl-
pyrazolidin-3-one crystallise out from the yellow filtrate.
A further 9.2 g of pure product are obtained by extracting
the residue with 500 ml of xylene. In total, 154.2 g
(viz. 62.3% of theory) of product having a melting point of
118 to 120C are obtained.
The thin layer chromatogram (solvent: chloroform/
methanol = 85:15) shows that the product obtained is a
single compound (rf 0.5).
The NMR spectrum corresponds to the expected struc-
ture. Elementary analysis:
calculated % C 64.06 found % C 63.51
H 6.84 H 7.00
N 13.58 N 13.30
Similarly good results are obtained when, in place
of ortho-phosphoric acid, phosphorus pentoxide, pyrophos-
phoric acid or an acid salt of ortho-phosphoric acid is
used as the catalyst.
Good results are also obtained, when only 0.6 mol
of phenylhydrazine are used instead of a total 2.4 mols.
Example 7: 750 ml of xylene and 1,081 g (10 mols) of
phenylhydrazine are initially introduced into a four-necked
round-bottomed flask of 3 l capacity, equipped with a ther-
mometer, stirrer, filling branch and reflux condenser with
a water separator. With stirring, 223.6 g (1.67 mols) of
2,2-~ishydroxymethylpropionic acid are introduced and the
mixture is heated to reflux on an oil bath. The tempera-
ture is then about 125 to 135C. The water formed is
separated off in the water separator. After 1 hour, a
further 223.6 g of the acid component are added, and another
223.6 g are added after a further hour. After a reaction
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time of about 7 hours, 85 ml of` water have formed. The
solvent is then distilled of~ under 150 to 200 mbars, and
the aniline formed by a side reaction and excess phenyl-
hydrazine are then distilled off under 20 mbars. A melt
of the intermediate 2,2-dihydroxymethylproplonic acid
phenylhydrazide remains at about 125 to 135C, and 35 g
(0.35 mol) of concentrated sulfuric acid are added thereto.
The melt is kept for 3 hours at 130C, and the water being
formed is continuously removed from the reaction mixture by
applying a vacuum of 50 to 60 mbars. After working up in
a mixture of water and isopropanol, l-phenyl-4-methyl-4-
hydroxymethyl-pyrazolidin-3-one is obtained in a yield of
61% (melting point: 114 to 120C).
C. Preparation of l-phenyl-4,4-dimethyl-pyrazolidin-3-one
.
Example 8: The procedure indicated in Example 6 is fol-
. .
lowed, except that, in place of 1.2 mols (in total) of 2,2-
bishydroxymethylpropionic acid, 1.2 mols of 2-methyl-2-
hydroxymethylpropionic acid are employed. The compound
of the formula
(102) CH3\ ~0
CH3 ~H
~,
,~ \.
11
~ /
can be isolated in yields of 64 . 7 % . (Melting point:
132 to 13~C).
D. Preparation of l-p-tolyl-4,4-dihydroxymethyl-pyrazolidin-
3-one
Example 9: In accordance with Example 7, 10 mols of p-
tolylhydrazine are reacted with 5 mols of tris-hydroxy-
methylacetic acid. The compound of the formula
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H-fH2 o
(103) HOCH2/l ~H
I!
~H3
can be isolated in a yield of 58%. (Melting point:
133 ~o 1~1C).
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