CA1165323A - Process for the preparation of pyrazolidin-3-ones - Google Patents
Process for the preparation of pyrazolidin-3-onesInfo
- Publication number
- CA1165323A CA1165323A CA000391818A CA391818A CA1165323A CA 1165323 A CA1165323 A CA 1165323A CA 000391818 A CA000391818 A CA 000391818A CA 391818 A CA391818 A CA 391818A CA 1165323 A CA1165323 A CA 1165323A
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- Prior art keywords
- acid
- process according
- hydrazide
- carried out
- formula
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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
- C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D231/08—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with oxygen or sulfur atoms directly attached to ring carbon atoms
-
- G—PHYSICS
- G03—PHOTOGRAPHY; CINEMATOGRAPHY; ANALOGOUS TECHNIQUES USING WAVES OTHER THAN OPTICAL WAVES; ELECTROGRAPHY; HOLOGRAPHY
- G03C—PHOTOSENSITIVE MATERIALS FOR PHOTOGRAPHIC PURPOSES; PHOTOGRAPHIC PROCESSES, e.g. CINE, X-RAY, COLOUR, STEREO-PHOTOGRAPHIC PROCESSES; AUXILIARY PROCESSES IN PHOTOGRAPHY
- G03C5/00—Photographic processes or agents therefor; Regeneration of such processing agents
- G03C5/26—Processes using silver-salt-containing photosensitive materials or agents therefor
- G03C5/29—Development processes or agents therefor
- G03C5/30—Developers
- G03C5/3028—Heterocyclic compounds
Abstract
Process for the preparation of pyrazolidin-3-ones Abstract In a one-vessel reaction or in two separate stages, pyrazolidin-3-ones are prepared by reacting a .beta.-hydroxy-propionic acid of the formula in which R2 is alkyl or hydroxyalkyl and R3 is hydroxyalkyl, with a phenylhydrazine of the formula in which R4 is hydrogen, alkyl, alkoxy, hydroxyl or halogen, to give a .beta.-hydroxypropionic acid hydrazide, and subse-quently cyclising the hydrazide. An acid catalyst is present during the cyclisation of the hydrazide and, optionally, even during its formation from the acid component and the hydrazine component.
The process leads to high yields of pyrazolidin-3-ones after a short reaction time.
The process leads to high yields of pyrazolidin-3-ones after a short reaction time.
Description
"~ ~ 1 6~323 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 ` ~k .
. . .
11 1 ~S323 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
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 ` ~k .
. . .
11 1 ~S323 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 in which R2 and R3 are as defined above, with a hydrazine of the formula~
(3) ~ NH-NH2 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 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
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 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
,, Ci~2-oH
1 ~ ~532~
in which R7 is methyl or hydroxymethyl, is reacted with a phenylhydrazine of the formula
(6) ~ NH-NH~
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
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
Preferably, in the process according to the inven-tion, a ~-hydroxypropionic acid of the formula
(8) Ho_cH2-~-cOOH
and phenylhydrazine are used for the preparation of the hydrazide of the formula ( 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 ~, ~ 135323 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.
....
~., 1 ~ 6~323 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 `` I 1 ~S323 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).
1 :~ 65323 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, 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, ~ 1 ~5323 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 -~ ~1 6~323 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
~, ,~ \.
~ /
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 .
H-fH2 o (103) HOCH2/l ~H
I!
~H3 can be isolated in a yield of 58%. (Melting point:
133 ~o 1~1C).
~: :
:~ .
,.
.. .
and phenylhydrazine are used for the preparation of the hydrazide of the formula ( 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 ~, ~ 135323 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.
....
~., 1 ~ 6~323 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 `` I 1 ~S323 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).
1 :~ 65323 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, 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, ~ 1 ~5323 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 -~ ~1 6~323 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
~, ,~ \.
~ /
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 .
H-fH2 o (103) HOCH2/l ~H
I!
~H3 can be isolated in a yield of 58%. (Melting point:
133 ~o 1~1C).
~: :
:~ .
,.
.. .
Claims (24)
1. A process for the preparation of a pyrazolidin-3-one of the formula (1) in which R1 is phenyl which is unsubstituted or substituted by alkyl or alkoxy each having 1 to 4 carbon atoms, hydroxyl or halogen, R2 is alkyl or hydroxyalkyl each having 1 to 4 carbon atoms and R3 is hydroxyalkyl having 1 to 4 carbon atoms, which comprises reacting a .beta.-hydroxypropionic acid of the formula (2) in which R2 and R3 are as defined above, with a hydrazine of the formula (3) in which R4 is hydrogen, alkyl or alkoxy each having 1 to 4 carbon atoms, hydroxyl or halogen, to give a .beta.-hydroxypro-pionic acid hydrazide and cyclising the latter, optionally in the same reaction mixture, in the presence of an acid catalyst.
2. A process according to claim 1, wherein the .beta.-hydroxy-propionlc acid hydrazide is cyclised in the same reaction mixture in the presence of an acid catalyst.
3. A process according to claim 1, wherein the formation of the hydrazide is also carried out in the presence of an acid catalyst.
4. A process according to claim 1, wherein the .beta.-hydroxy-propionic acid is of the formula (4) in which R5 is methyl, ethyl, hydroxymethyl or 1- or 2-hy-droxyethyl and R6 is hydroxymethyl or 1- or 2-hydroxyethyl.
5. A process according to claim 4, wherein the .beta.-hydroxy-propionic acid is of the formula (5) in which R7 is methyl or hydroxymethyl.
6. A process according to claim 1, wherein the hydrazine is of the formula (6) in which R8 is hydrogen, methyl, methoxy, hydroxyl or chlorine.
7. A process according to claim 6, wherein the hydrazine is of the formula (7) in which R9 is hydrogen, methyl or methoxy.
8. A process according to claim 1 for the preparation of l-phenyl-4-methyl-4-hydroxymethylpyrazolidin-3-one, which comprises reacting phenylhydrazine with 2,2-bishydroxy-methylpropionic acid and then effecting cyclisation of the phenylhydrazide of the 2,2-bishydroxymethylpropionic acid so obtained.
9. A process according to claim 1, wherein the formatlon of the hydrazide and the cyclisation are carried out at temperatures from 100 to I60° C.
10. A process according to claim 9, wherein the temperatu-re is 110 to 140° C.
11. A process according to claim 10, wherein the temperature is 120 to 140°C.
12. A process according to claim 11, wherein the tem-perature is 125 to 135°C.
13. A process according to claim 1, wherein the carboxylic acid component and the hydrazine com-ponent are employed in a molar ratio of 2:1 to 1:5.
14. A process according to claim 13, wherein the ratio is 1:1 to l:3.
15. A process according to claim 14, wherein the molar ratio is 1:1.5 to 1:2.5.
16. A process according to claim 1, wherein the cycli-sation of the hydrazide is carried out without an acid catalyst, if the molar ratio of the carboxylic acid component to the hydrazine component is 1.5:1 to 2:1.
17. A process according to claim 1, wherein the cyclisation of the hydrazide is carried out in the presence of hydrogen chloride, hydrogen bromide, ortho-phosphoric acid, polyphosphoric acid, phosphorus pentoxide, pyrophosphoric acid or an acid salt of ortho-phosphoric acid, or in the presence of benzenesulfonic acid, p-toluene-sulfonic acid, methanesulfonic acid, carbon dioxide, sulfur dioxide or sulfuric acid.
18. A process according to claim 17, wherein the cycli-sation is carried out in the presence of hydrogen chloride, hydrogen bromide, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, carbon dioxide, sulfur dioxide or sulfuric acid.
19. A process according to claim 18, wherein the cycli-sation is carried out in the presence of hydrogen chloride or methanesulfonic acid.
20. A process according to claim 17, wherein the cycli-sation is carried out in the presence of ortho-phosphoric acid.
21. A process according to claim 1, wherein the formation and cyclisation of the hydrazide are carried out in a solvent.
22. A process according to claim 21, wherein the solvent used is xylene, toluene, chlorobenzene. 1,2-dichlorobenzene or ethylbenzene.
23. A process according to claim 1, wherein the formation and cyclisation of the hydrazide are carried out in the melt at 125 to 135°C.
24. A process according to claim l, wherein the formation of the hydrazide is carried out in a solvent and the cyclisation of the hydrazide is carried out in the melt at 125 to 135°C.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH9100/80-0 | 1980-12-10 | ||
| CH910080 | 1980-12-10 | ||
| CH387981 | 1981-06-12 | ||
| CH3879/81-0 | 1981-06-12 | ||
| CH5262/81-1 | 1981-08-14 | ||
| CH526281 | 1981-08-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1165323A true CA1165323A (en) | 1984-04-10 |
Family
ID=27174581
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000391818A Expired CA1165323A (en) | 1980-12-10 | 1981-12-09 | Process for the preparation of pyrazolidin-3-ones |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP0054002B1 (en) |
| CA (1) | CA1165323A (en) |
| DE (1) | DE3171947D1 (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0134696A1 (en) * | 1983-08-04 | 1985-03-20 | EASTMAN KODAK COMPANY (a New Jersey corporation) | Preparation of 4-substituted-3-pyrazolidinones |
| US4481287A (en) * | 1983-08-04 | 1984-11-06 | Eastman Kodak Company | 4-Hydroxyalkyl-substituted 3-pyrazolidinone electron transfer agents |
| US4471045A (en) * | 1983-08-04 | 1984-09-11 | Eastman Kodak Company | 4-Hydroxyalkyl-substituted 3-pyrazolidinone electron transfer agents |
| US6783766B2 (en) | 2002-03-06 | 2004-08-31 | Dow Global Technologies Inc. | Process for preparing a cosmetic formulation |
| EP2112139A1 (en) * | 2008-04-25 | 2009-10-28 | Laboratorios Del. Dr. Esteve, S.A. | Process for the preparation of naphthalen-2-yl-pyrazol-3-one intermediates useful in the synthesis of sigma receptor inhibitors |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1093281A (en) * | 1963-03-22 | 1967-11-29 | Kodak Ltd | 3-pyrazolidones and their use as photographic developers |
| GB1157617A (en) * | 1965-09-09 | 1969-07-09 | Kodak Ltd | Method of making 3-Pyrazolidones |
| US4209580A (en) * | 1978-10-02 | 1980-06-24 | Eastman Kodak Company | Substituted 1-phenyl-3-pyrazolidinone electron transfer agents |
-
1981
- 1981-12-04 DE DE8181810476T patent/DE3171947D1/en not_active Expired
- 1981-12-04 EP EP19810810476 patent/EP0054002B1/en not_active Expired
- 1981-12-09 CA CA000391818A patent/CA1165323A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| EP0054002A1 (en) | 1982-06-16 |
| EP0054002B1 (en) | 1985-08-21 |
| DE3171947D1 (en) | 1985-09-26 |
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