DE1064067B - Process for the preparation of the therapeutically effective 1,2-diphenyl-3,5-dioxo-pyrazolidines substituted in the 4-position by a gamma- or delta-oxybutyl radical - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

kl. 12 p 8/01

INTERNAT. KL. C 07

PATENT OFFICE

EXPLAINING PUBLICATION 1064 067

G17949 IVb / 12p

REGISTRATION DATE: SEPTEMBER 9, 1955

NOTICE
THE REGISTRATION
AND ISSUE OF THE
EXPLORATION PAPER: 2 Y. AU GU ST 19 5 9

The invention relates to a process for the preparation of the therapeutically valuable 1,2-diphenyl-3,5-dioxo-pyrazolidines substituted in the 4-position by a γ- or <5-oxybutyl radical and their salts with inorganic and organic bases. 1,2-Diphenyl-4-n-butyl-3,5-dioxo-pyrazolidine has gained great importance as a drug for the treatment of rheumatic diseases.

Some 1 ^ -diphenyl-S.S-dioxo-pyrazolidines are known from German patent 903 578 hydrocarbon radicals interrupted in the 4-position by heteroatoms (e.g. oxygen) or heteroatom groups wear, e.g. B. the / J-acetoxyethyl group. These connections have favorable analgesic and antipyretic properties, some also have anti-inflammatory properties on. As an intermediate product for the preparation of such compounds with oxygen as a hetero atom, the German Patent 903 578 also 1,2-diphenyl-4 - (/ 3-oxyethyl) -3,5-dioxo-pyrazolidine mentioned, which has no anti-inflammatory activity.

As has now been found, surprisingly, 4- (y-oxybutyl) - and 4- (<5 ~ oxybutyl) -l, 2-diphenyl-3,5-dioxo-pyrazolidine have therapeutically interesting properties, in particular excellent anti-inflammatory and uricosuric ( uric acid flushing) effectiveness, so that these two compounds are particularly suitable for the treatment of gout in humans. They are relatively little toxic (DLg ₀ 620 to 675 mg / kg iv in the mouse).

These two new compounds can be prepared in a manner known per se by ring-closing condensation of reactive functional derivatives of malonic acids which, in the α-position, have a substituent which can be converted into a γ or (5-oxybutyl radical by hydrolysis and / or by reduction or by hydrogenolysis) contain, with hydrazobenzene or with N-acylhydrazobenzenes or other reactive N-substituted hydrazobenzene derivatives and subsequent conversion of the substituent now in the 4-position of the pyrazolidine ring into a γ- or o-oxybutyl group -oxybutyl-substituted malonic acid diesters with hydrazobenzene or N-substituted derivatives thereof directly to the corresponding 1 ^ -diphenyl ^ -oxybutyl-SS-dioxo-pyrazolidines.

The following can be considered as modifications to the method generally defined above:

a) As malonic acid derivatives

Sl ₁ ) substituted malonic acid diesters of the general formula

Process for the production of the therapeutically effective,

1,2-diphenyl -3,5- dioxo - pyrazolidine substituted in the 4-position by a γ- or δ-oxybutyl radical

Applicant: J. R. Geigy A.-G., Basel (Switzerland)

Representative: Dr. K. Griesing, patent attorney, Hönebach bei Bebra, Bahnhofstr. 9

Claimed priority: Switzerland of September 10, 1954

Dr. Rolf Denss, Dr. Rudolf Pfister and Dr. Franz Häfliger, Basel (Switzerland), have been named as inventors

CO-O-X

R-CH

CO-O -X

where R is a radical which can be converted into a γ- or (5-oxybutyl radical) by hydrolysis and / or reduction or by hydrogenolysis and X is radicals that can be easily split off, in particular lower alkyl radicals; a ₂ ) substituted malonic acid derivatives in general

formula
45

R-CH

CO-Y

J-

in which R has the meaning given above and Y is chlorine, bromine or an acyloxy radical;

909 609/414

a ₃ ) substituted malonic acid ester derivatives of the general formula

CO-Ο —Χ

R-CH

III

respectively

R-C

CO-Y

CO-O -X

C = O

wherein R, X and Y have the meanings given above;

a ₄ ) Dialkyl ester of <5-oxybutylmalonic acid.

b) As hydrazobenzenes

Hydrazobenzene itself or reactive hydrazobenzenes substituted in the hydrazine group; than theirs Substituents: easily split off residues, such as acid residues (acetyl residue), alkali metal atoms, alkaline earth metal monohalide residues.

If acid is released as a result of the reaction, the addition of acid-binding agents is recommended; will Alcohol free, the presence of condensing agents, such as metal alcoholates, is beneficial. If the reaction takes place in stages, such as B. with ester halides, these agents are used one after the other.

If an intermediate is formed in which the radical R has remained unchanged, it is then converted into the radical HO - C ₄ H ₈ - or CH ₃ - CHOH - C ₂ H ₄ - by hydrolysis and / or reduction or by hydrogenolysis.

The choice of the starting materials of the general formulas I and II and thus those for converting the intermediate products the general formula

CO-N-phenyl

R-CH j V

^ CO- Ν - phenyl

in which R has the meaning given above, in the hydrolysis and / or reduction processes necessary for the end products depend in particular on the distance between the hydroxyl groups present in the end product and the pyrazolidine ring as well as whether they are primary or secondary in nature. While by hydrogenolysis, ζ. Β. of benzyloxy-alkyl compounds, hydroxyl groups introduced at any distance from the pyrazolidine ring, d. H. can be set free, the mere hydrolysis leads to the introduction of hydroxyl groups in y-position because of the difficulty of manufacture related starting materials while avoiding lactonization less into consideration.

For the production of the end product with a cS-oxybutyl group on the other hand, starting materials can advantageously be used, which can be obtained by simple hydrolysis contain group convertible to the oxy group. The hydroxyl group can e.g. B. be esterified, more advantageous it is, however, when it is bound like an acetal, since in this case it condenses in the alkaline medium is better protected, but can be easily released afterwards by acid hydrolysis.

The oxygen-containing groups which can be converted into hydroxyl groups by simple reduction are free oxo groups and also, if appropriate, carboxyl groups and halogenoformyl groups (acid halides). The groups which can be converted into the hydroxyl group by hydrolysis and reduction are the carbalkoxy groups and also called acetalized oxo groups. The 5 oxo group can be monovalent with two molecules Alcohol as well as with a molecule of a glycol, most advantageously with ethylene glycol, to form an acetal group be connected.

By means of these process modifications mentioned here

ίο the ring-closing condensation gives pyrazolidine derivatives, which already contain the carbon structure of the side chain in the 4-position, albeit mostly not the finished oxybutyl group.

A possibility for the subsequent introduction of the oxybutyl group in the 4-position of 1,2-diphenyl-3,5-dioxopyrazolidine is that this compound with an aliphatic oxo compound of general formula

R '= O VI

wherein R 'denotes a geminal divalent radical corresponding to a radical R defined above and leaned by one hydrogen atom Radical means, or with a functional derivative of such an oxo compound, in particular one Acetal, alcoholate or enol ether, condensed and simultaneously or subsequently catalytic, ζ. Β. by means of precious metal catalysts or Raney nickel, activated hydrogen can act, expediently at the same time Reduction or hydrogenolysis of an optionally present in the radical R ', in this way into the Hydroxyl group convertible oxygen-containing group, and optionally then a hydrolyzable group Group of the radical R 'hydrolyzed and the hydrolysis product, if it does not already contain the hydroxyl group, reduced. Suitable starting materials of the general formula R '= O are, for example, benzyloxybutylaldehydes, Acetals, diacetals and enol ethers of dioxobutanes and dioxobutenes, such as. B. 1,1-dimethoxy-butan-3-one, 1,1,3,3-tetramethoxybutane, l-methoxy-buten- (1) -one- (3) and 1,3,3-trimethoxybutene- (1).

The new 1,2-diphenyl-4-oxybutyl-3,5-dioxo-pyrazolidine are colorless crystalline substances that are found both in common organic solvents as well, as a result Presence of an acidic hydrogen atom, easily dissolving as an enolate ion in dilute, aqueous alkalis and easily form monobasic salts with other inorganic as well as organic bases.

In this connection, reference should be made to a peculiarity of the γ-oxybutyl compound. While in the salts of this compound or their aqueous solutions there is always a tautomeric form of 4- (y-oxy-butyl) -l, 2-diphenyl-3,5-dioxopyrazolidine is present, the free 4- (y-oxy-butyl) -l, 2-diphenyl) -3,5-dioxo-pyrazolidine into the Ν, Ν'-diphenylhydrazide of the corresponding lactonecarboxylic acid, d. H. into the <5-caprolactone-a-carboxylic acid Ν, Ν'-diphenyIhydrazide the formula

CH ₉ -CH

CO - N - phenyl
NH-phenyl

CH,

CH - O

CH ₃

rearrange. The rearrangement often takes place so easily that when the crude product is worked up in the usual way, i. H. in the Recrystallization from an organic solvent gives the lactone form of formula VII. The same thing is the case when you run out of alcoholic solutions

Alkali salts of 4- (γ-oxybutyl) -l, 2-diphenyl-3,5-dioxopyrazolidine the dioxopyrazolidine on which they are based is released by acidification and then not quickly separates. The lactone compound of the formula VII is not soluble as such in aqueous bases, but it works gradually with rearrangement into salts of a tautomeric form of the y-oxybutyl-dioxopyrazolidine compound in Solution.

The lactone compound VII has a higher melting point than the free γ-oxybutyl-dioxopyrazolidine compound.

The lactone compound of the formula VII is obtained by dissolving it in an alkaline medium, in particular aqueous or aqueous-alcoholic alkali metal hydroxide solutions, alkali metal salt solutions of the γ-oxybutyldioxopyrazolidine compound and from this by acidification and rapid separation of the precipitated substances the free γ-oxybutyl-dioxopyrazolidine compound.

The following examples are intended to explain the preparation of the two new compounds in more detail. In it, parts mean parts by weight; these relate to parts by volume as g to cm ³ .

example 1

a) 1,2-Diphenyl-4- (3 ', 3'-ethylenedioxy-butyl) -3,5-dioxo-pyrazolidine

274 parts of (3,3-ethylenedioxy-butyl) malonic acid diethyl ester are abs in 100 parts by volume. Benzene dissolved and 57 parts of sodium methylate and 184 parts of hydrazobenzene are added. Warming occurs. the The reaction mass is refluxed for 15 hours. After cooling, it is poured into water, separated off and the aqueous portion washed twice with benzene. The benzene solutions are used three times Washed 2N soda solution and the combined aqueous solutions acidified with 2N hydrochloric acid. The failed 1,2-diphenyl-4- (3 ', 3'-ethylenedioxy-butyl) -3,5-dioxo-pyrazolidine can be recrystallized from alcohol. Mp. 165 to 167 ° C.

b) 1,2-diphenyl-4- (3'-oxobutyl) -3,5-dioxo-pyrazolidine

36.6 parts of 1,2-diphenyl-4- (3 ', 3 ^/ -äthylenedioxy-butyl) -3,5-dioxopyrazolidine are refluxed in 750 parts by volume of acetone with 0.35 parts of p-toluenesulfonic acid for 18 hours. The solution is then filtered, 1500 parts of water are added and the mixture is left to stand at 5 ° C. for 24 hours. The precipitated 1,2-diphenyl-4- (3'-oxobutyl) -3,5-dioxo-pyrazolidin is suction filtered and washed with 50 ° / ₀ acetone. Mp. 115.5 to 116.5 ° C from an alcohol-water mixture. Occasionally a crystal form melting at 127.5 to 128.5 ° C is obtained.

c) 1,2-Diphenyl-4- (3'-oxybutyl) -3,5-dioxo-pyrazolidine

By reduction with sodium borohydride: 50 parts of 1,2-diphenyl-4- (3'-oxobutyl) -3,5-dioxo-pyrazolidin be 1300 parts by volume of methanol and 171 parts by volume of 1 dissolved η sodium hydroxide solution and 250 parts by volume of 10 ° / ₀ methanolic Sodium borohydride solution added. This solution is left to stand for 24 hours, it being ensured by cooling with water that the temperature does not exceed 40.degree. It is then filtered and 2500 parts by volume of 2N hydrochloric acid are added. After 48 hours of standing at 5 ° C., the mixture is filtered off with suction and the 1,2-diphenyl-4- (3'-oxy-butyl) -3,5-dioxo-pyrazolidine is washed with 50% strength methanol. Mp from acetone: 163 to 164 ° C.

From the aqueous-methanolic mother liquor, additional amounts of can be extracted by shaking with chloroform End product can be obtained.

The crystallized compound with a melting point of 163 to 164 ° C is the <5-caprolactone-a-carboxylic acid-N, N'-diphenylhydrazide It is rather difficult to dissolve in alcohol, somewhat more easily in acetone, and even more easily in chloroform. In the cold, aqueous or alcoholic-aqueous alkalis do not dissolve until after hours of shaking. The dissolution process can be significantly accelerated by gentle heating. From the alkaline-aqueous Solution becomes that through rapid precipitation with acid

ίο obtained 1,2-diphenyl-4- (3'-oxy-butyl) -3,5-dioxo-pyrazolidine, which ^{melts at 89 to 91 0} C and dissolves very easily in alcohol and acetone and also in aqueous alkalis. The compound of mp is again by crystallization from alcohol and acetone. Receive 163-164 ⁰ C.

Reaction is carried out in the above example in aqueous place in aqueous-methanolic solution so obtained which melts at 89 to 91 ⁰ C, highly alkali-soluble Dioxopyrazolidinverbindung the precipitation with 2N hydrochloric acid immediately, by recrystallization from z. B. acetone can be converted into the lactone compound melting at 163 to 164 ° C.

Catalytic reduction: 5 parts of 1,2-diphenyl-4- (3'-oxobutyl) -3,5-dioxopyrazolidine are dissolved in 100 parts of alcohol and 50 parts of 1N NaOH and with 5 parts of nickel catalysts (Raney) with ordinary Temperature and normal pressure _{shaken in an H 2} atmosphere. After the calculated amount of H _{2 has been} absorbed, the hydrogenation practically comes to a standstill. The catalyst is filtered off and 50 parts of 2N HCl are added to the filtrate. After standing for several days at 5 ° C., the precipitated 1,2-diphenyl-4- (3'-oxybutyl) -3,5-dioxopyrazolidine is filtered off with suction and washed out with 50% alcohol. The product is identical to that produced by reduction with NaBH ₁ .

Example 2

a) 1,2-Diphenyl-4- (4'-tetrahydropyranyl- (a) -oxybutyl) -

3,5-dioxo-pyrazolidine
40

25 parts of 4- (tetrahydropyranyl- (α) -oxy) -butyl-malonic acid diethyl ester (made from (4-oxy-butyl) malonic acid diethyl ester, Dihydropyran and a little concentrated hydrochloric acid) are abs in 15 parts by volume of benzene.

dissolved and refluxed for 12 hours with 4.5 parts of sodium methylate and 14.9 parts of hydrazobenzene. The cooled reaction mass is poured into ice water, separated off and the aqueous portion extracted twice with benzene. The benzene solutions are washed three times with 2N soda solution and the combined aqueous solutions are acidified with ice-cold 2N hydrochloric acid. The precipitated 1,2-diphenyl-4- (4'-tetrahydropyranyl - (α) - oxy - butyl) - 3,5 - dioxo - pyrazolidine melts after recrystallization from alcohol at 123 to 124 ⁰ C. It can also from one of the Malonic acid derivatives mentioned under a ₂ ) to a ₄ ) in the introduction to the description are prepared.

b) 1,2-Diphenyl-4- (4'-oxybutyl) -3,5-dioxo-pyrazolidine

50 parts 1,2-diphenyl-4- (4'-tetrahydropyranyl- (a) -oxybutyl) -3,5-dioxo-pyrazolidine are dissolved in 2300 parts by volume of alcohol and 200 parts by volume of 2N sulfuric acid are added in the cold. The solution is 7 hours left to stand for a long time at room temperature and then diluted with 4000 parts by volume of water. After 48 hours The 1,2-diphenyl-4- (4'-oxybutyl) -3,5-dioxo-pyrazolidine which has crystallized out will stand in the refrigerator Sucked off, washed with water and dried. It can be made from about 25% alcohol (dissolve in a little alcohol and add recrystallized with water until the onset of turbidity)

will. The compound melts at 104 to 105 ^° C., solidifies again and finally melts at 114 to 115 ^° C.

Example 3

1,2-diphenyl-4- (4'-oxy-butyl) -3,5-dioxo-pyrazolidine from (4-oxy-butyl) malonic acid diethyl ester

18 parts (4-oxybutyl) malonic acid diethyl ester will be dissolved in 20 parts by volume of benzene and mixed with 4.5 parts of sodium methylate and 14.9 parts of hydrazobenzene for 12 hours long refluxed. After cooling, it is poured into water and the aqueous phase is washed with benzene. When acidified with dilute hydrochloric acid, it gives an oil that is absorbed into ether. The ether is washed neutral with water, dried over sodium sulfate and distilled off. The oily residue can be recrystallized from alcohol-water or benzene-petroleum ether mixture. M.p. 114 to 115 ° C.

Claims (1)

Claim: Process for the preparation of the therapeutically active l ^ -diphenyl-SS-dioxo-pyrazolidines substituted in the 4-position by a γ- or <5-oxybutyl radical and salts thereof, characterized in that a substituted malonic acid diester of the general formula R-CH CO-O -X CO-O-X in which R is a radical which can be converted into a γ- or <5-oxybutyl radical by hydrolysis and / or reduction or by hydrogenolysis and X is a radical which can be easily split off, or a substituted malonic acid derivative of the general formula R-CH CO-Y CO-Y II 40 wherein R has the meaning given above and Y is chlorine, bromine or an acyloxy radical, or a substituted malonic acid ester derivative of the general formula CO-0 -X R-CH III CO-Y respectively ^ CO-OX
RC IV in which R, X and Y have the meaning given above, or a dialkyl ester of <5-oxybutylmalonic acid act on hydrazobenzene or an N-substituted, reactive hydrazobenzene derivative leaves, optionally in the presence of acid-binding or condensing agents or 1,2-diphenyl-3,5-dioxopyrazolidine with an aliphatic oxo compound of the general formula R '= O VI where R 'denotes a geminally divalent radical corresponding to the radical R defined above, lesser by one hydrogen atom, or condensed with a functional derivative of such an oxo compound, in particular an acetal, alcoholate or enol ether, and simultaneously or subsequently allowing catalytically activated hydrogen to act, expediently with simultaneous reduction or hydrogenolysis of an oxygen-containing group which may be present in the radical R 'and which can be converted into the hydroxyl group in this way, and in the resulting pyrazolidine, if it contains the radical R as defined above, this by hydrolysis and / or by reduction or by hydrogenolysis in the γ- or o-oxybutyl radical and optionally converted the compounds obtained into their salts with inorganic or organic bases. Considered publications:
German patent specification No. 814150. © 909 609/414 8.59