DE1081017B - Process for the preparation of therapeutically effective 4-substituted 1, 2-diphenyl-3, 5-dioxy-pyrazolidines - Google Patents

Description

GERMAN

The invention relates to the preparation of therapeutically effective 4-substituted 1,2-diphenyl-3,5-dioxopyrazolidines the general formula

/ CO-N-Ar ₁
R —CO —CH; I.

"CO-N-Ar ₂

or their tautomeric forms, in which R denotes an aliphatic, aromatic, araliphatic or cycloaliphatic hydrocarbon radical which can be interrupted by - CO - O - and in which an aromatic hydrocarbon radical can be substituted by hydroxyl or low molecular weight alkoxy groups, and Ar ₁ and Ar ₂ Phenyl radicals which can be substituted by low molecular weight alkyl or hydroxyl groups. These compounds can be prepared in a simple manner by using a reactive functional derivative of a carboxylic acid of the general formula Process for Preparation
of therapeutically effective

4-substituted 1,2-diphenyl-3,5-dioxypyrazolidines

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

Representative: Dr. F. Zumstein
and Dipl.-Chem. Dr. rer. nat. E. Assmann,
Patent Attorneys, Munich 2, Bräuhausstr. 4th

Claimed priority:
Switzerland from December 16, 1954

R-COOH

II

or the free carboxylic acid to a 1,2-diphenyl-3,5-dioxopyrazolidine the general formula

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

CH,

XO-N-Ar ₁

XO-N-Ar ₉

III

or the general formula

, XO - N - Ar /
H ₂ C ('

XO-N-Ar ₅ ,

IV

wherein Ar ₁ 'is an aralkyloxyphenyl radical, in particular the benzyloxyphenyl radical, and Ar ₁ , Ar ₂ and R are as defined above, optionally in the presence of a basic condensing agent, and, if reacted with a compound of the formula IV, the condensation product by means of hydrogenolyzed catalytically activated hydrogen. The compounds of general formula I which can be prepared according to the invention have valuable therapeutic properties, in particular anti-inflammatory and antipyretic activity. A particularly advantageous process modification for their preparation is the condensation of a carboxylic acid halide or anhydride with a compound of the general formula III in the presence of pyridine or another tertiary organic base, and also in the presence of inorganic basic condensing agents, e.g. B. potassium carbonate. Furthermore, carboxylic acid esters can also be used in the presence of alkali metal alcohol-2

Laten to react with compounds of the general formula III arrive. In particular acid anhydrides, z. B. acetic anhydride, but also acid halides can when heated with compounds of the general Formula III react in the desired sense even in the absence of condensing agents.

While the addition of a solvent is often unnecessary when using acid anhydrides, the Reactions with acid halides with advantage in inert organic solvents, e.g. B. in benzene or Chloroform. Reactions with carboxylic acid esters can take place, for example, in alcohols be carried out at a suitable boiling point or in inert organic solvents.

The new 1,2-diphenyl-3,5-dioxo ~ 4-acylpyrazolidines are mostly colorless crystallized compounds. With Inorganic and organic bases they form salts, some of which are very sparingly soluble.

From German patents 668 387 and 676 Sl 3 1,2,3-substituted 5-pyrazolones have already become known, which carry an acyl group in the 4-position. Furthermore, l, 2-diaryl-3,5-dioxopyrazolidines are known, which are substituted in the 4-position by an aliphatic side chain, which optionally by heteroatoms can be interrupted; which falls under this group has 1,2-diphenyl-3,5-dioxo-4-n-butylpyrazolidine gained great importance as a drug for the treatment of rheumatic diseases.

009 50 & / 399

3 4

The obtained by the process according to the invention- washed with dilute hydrochloric acid and with water and

borrowed in the 4-position substituted by acyl groups evaporated. The extracted crystals are collected together

l, 2-Diaryl-3,5-dioxopyrazolidines have not yet been treated with the evaporation residue twice from hydrochloric acid

known and become characterized by good anti- mooch aqueous alcohol and then comprised 80 ° / ₀ sodium

phlogistic effectiveness and much lower toxicity. The l ^ -diphenyl ^ -caproyl-

ity from. 3,5-dioxopyrazolidine melts at 92 to 93 ° and be

The following examples are intended to produce the 2,4-dinitrophenylhydrazone at 172 to 174 °.

explain new connections in more detail. Parts mean In an analogous manner one obtains z. B. the 1,2-diphenyl

therein parts by weight, these are related to parts by volume of 4-valeryl-3 ₎ 5-dioxopyrazolidine _J F. 66.5 to 67.5 °; 1,2-di

how grams to cubic centimeters. The temperatures 10 phenyl-4-isovaleryl-3,5-dioxopyrazolidine, mp 103 to 104 °;

are given in degrees Celsius. 1,2-diphenyl-4- (j5-phenyl-propionyl) -3,5-dioxopyrazolidine)

• D · · "1 1 F. 115.5 to 116.5 °; l ^ -Diphenyl-l-cinnamoyl-S.S-dioxo-

Example 1 pyrazolidine, mp 181.5-182.5 °; | 1,2-diphenyl-4-iso-

25.2 parts of 1,2-diphenyl-3,5-dioxopyrazolidine are butyryl-3,5-dioxopyrazolidine, melting point 110 to 112 °, and 1,2-bis

mixed with 32 parts by volume of pyridine and 22.6 volumes of 15 (p-methyl-phenyl) -4-benzoyl-3,5-dioxopyrazolidine, F. 154

parts of acetic anhydride added. Under self-heating up to 155 °.

A homogeneous solution is formed from which in Example 5 The pyridine salt of the l ^ -diphenyl ^ -acetyl-

3,5-dioxopyrazolidines in yellow crystals auskristalli- 50.4 parts of l, 2-diphenyl-3,5-dioxopyrazolidine are in

sated. It is stirred with benzene, sucked off and with _a o 400 parts by volume of benzene and 70 parts by volume of pyridine

Washed out benzene. This can be suspended from the pyridine salt and then 38.1 parts of di-n-butyl acetyl chloride

l ^ -DiphenyM-acetyl-SjS-dioxopyrazolidine z. B. by adding in 40 parts by volume of benzene with stirring,

prolonged heating at 10 to 15 mm pressure to 80 to 90 ° Then heated to boiling for 10 minutes and

can be obtained. After crystallization from alcohol or afterwards for 4 hours at room temperature,

Sublimation at 0.002 mm Hg pressure, colorless 25 are stirred. It is sucked off from the precipitate, the

Crystals with a melting point of 117 to 118 ° were obtained. The same compound benzene solution was washed with hydrochloric acid and water

manure is also evaporated when 1,2-diphenyl- and boiling for 3 hours. The evaporation residue becomes some

3,5-dioxopyrazolidine with acetic anhydride without condensation- Male with saturated sodium bicarbonate solution under

sation means formed. Stir extracted and the insoluble fraction finally

. 30 recrystallized from aqueous alcohol containing hydrochloric acid.

Example 2 _{The SQ obtained} l ^ DihM ^ bll ^ Sdi

25.2 parts of 1,2-diphenyl-3,5-dioxopyrazolidine are in oxopyrazolidine, melting at 88 to 90 °.

32 parts by volume of pyridine and 200 parts by volume of benzene Analogously to the previous example, z. B.

suspended and with stirring 11.5 parts of butyryl chloride and the 1,2-diphenyl-4- (a-cycloheptenyl-butyryl) -3,5-di-

benzene was added dropwise in 12 parts by volume. The temperature 35 oxopyrazolidine, m.p. 108.5 to 109.5 °, and the 1,2-diphenyl

increases to 40 to 50 °. Without external heat supply, 4-homoveratroyl-3,5-dioxopyrazolidine, mp 148.5 ° to 150.5 °

is stirred for about another 5 hours, then from (recrystallized from benzene). precipitated pyridine hydrochloride filtered off and the

Benzene solution with 2N hydrochloric acid and then with Example 6

Water washed. After distilling off the 40 14.1 parts of benzoyl chloride are in 15 parts by volume

The residue remaining in the solvent can be dissolved over benzene and given a suspension of 35.8 parts

the sodium salt, which is sparingly soluble in water, purified l- (p-benzyloxyphenyl) -2-phenyl-3,5-dioxopyrazolidine

will. The pure, from petroleum ether-benzene mixture or (made from p-benzyloxyhydrazobenzene and malon

Dilute alcohol crystallized (^ -diphenyl ^ -butyryl acid diethyl ester, m.p. 185 to 190 °, with decomposition),

3,5-dioxopyrazolidine melts at 79 to 80 °. The melting point is 45 250 parts by volume of benzene and 35 parts by volume of pyridine

point of the semicarbazone is 207 to 208 °. added dropwise with stirring. After the reaction has ended

. . is suctioned off and the alcohol precipitate is

Example ό crystallized, m.p. 116 to 117 °. 23.1 parts of the thus obtained

31.0 parts of phenylacetic acid chloride are dissolved in 30 parts by volume of l- (p-benzyloxyphenyl) -2-phenyl-4-benzoyl-3,5-dioxopyr parts of benzene and, with stirring, in a mixture of 50 parts by volume of 1 η sodium hydroxide solution and dissolved from 50.4 parts of 1,2-diphenyl-3,5-dioxopyrazolidine, 70 parts by volume of 800 parts by volume of alcohol and catalyst (Raney nickel) added dropwise with 20 parts of nickel parts by volume of pyridine and 400 parts by volume of benzene. It is shaken in the cold for about 14 hours at normal pressure in an H ₂ atmosphere. After further stirring, filtered and the benzene solution as in the absorption of the calculated amount of hydrogen (1 mole of Example 2 with dilute hydrochloric acid and water per mole of starting material) wash the hydrogen uptake. That practically comes to a standstill after the solution has been distilled off. The catalyst is filtered off using the remaining l ^ -DiphenyW-phenacetyl-SS-di- and 250 parts by volume of oxopyrazolidine are added, while cooling with ice, and the mixture is melted, recrystallized from alcohol, with 2 η-hydrochloric acid and 100 parts by volume of water. After 112.5 to 113.5 °. When the crystallization has ended, it is filtered off with suction and crystallized

In an analogous manner, for. B. the l, 2-bis- (p-methyl- 60 the l- (p-oxyphenyl) -2-phenyl-4-benzoyl-3,5-dioxopyr-

phenyl) -4-phenacetyl-3,5-dioxo-pyrazolidin F. 149 to azolidine of 80 ° / ₀ ° alcohol to what is at 198 to

151 °, and the 1,2-bis- (p-methyl-phenyl) -4-isobutyryl- 200 ° melts.

3,5-dioxopyrazolidine, m.p. 106-108 °, can be prepared. In an analogous manner one obtains z. B. also the l- (p-

. Benzyloxyphenyl) -2-phenyl-4-phenacetyl-3,5-dioxopyr-

üebeispiel 4 ^ _{azolidill) F 10} 3 to 106 °, and the l- (p-oxyphenyl) -2-phe-

- 50.4 parts of 1,2-diphenyl-3,5-dioxopyrazolidine are nyl ^ -phenacetyl-S.S-dioxopyrazolidine, mp 155 to 157 °.

in 400 parts by volume of benzene and 70 parts by volume of pyridine. .

suspended and then 26.9 parts of caproyl chloride in Example 7

25 parts by volume of benzene were added dropwise. After completion of 13.4 parts of l- (p-oxyphenyl) -2-phenyl-3,5-dioxopyrazo-

The reaction is suctioned off and the benzene mother liquor 70 lidine (made from the I- (p-benzyloxyphenyl) -2-phe-

nyl-3,5-dioxopyrazolidine by hydrogenolysis analogous to the method of Example 6, mp 175 to 185 °) suspended in 100 parts by volume of benzene and 17 parts by volume of pyridine, whereupon 5.4 parts of butyryl chloride, dissolved in 5 parts by volume of benzene. The reaction mixture is about 14 hours stirred further at room temperature and then the precipitate was filtered off with suction and stirred at 500 parts by volume 2 N sodium carbonate solution extracted. The sodium carbonate extract is filtered and then with charcoal acidified with 2η hydrochloric acid while cooling with ice, the precipitate which has separated out is filtered off with suction and removed recrystallized aqueous alcohol. The l- (p-oxyphenyl) -2-phenyl-4-butyryl-3,5-dioxopyrazolidine melts at 144 to 146 °.

The above compound can also be obtained by hydrogenolysis of l- (p-benzyloxyphenyl) -2-phenyl-4-butyryl-3,5-dioxopyrazolidine, F. 91 to 93 °, analogously to Example 6 manufacture.

Example 8

20th

25.2 parts of 1,2-diphenyl-3,5-dioxopyrazolidine are in 200 parts by volume of chloroform and 35 parts by volume of pyridine dissolved and then 14.1 parts of benzoyl chloride in 15 parts by volume of chloroform were added dropwise with stirring. Well will the reaction mixture heated to boiling for 30 minutes, then allowed to cool and repeatedly with 2N hydrochloric acid and water, dried with sodium sulfate and evaporated, the evaporation residue is several times extracted while stirring with saturated sodium bicarbonate solution. From the combined alkaline extracts When acidifying with dilute hydrochloric acid, 1,2-diphenyl-4-benzoyl-3,5-dioxopyrazolidine separates, which after Recrystallization from alcohol at 109.5 to 110.5 ° melts. The melting point of its 2,4-dinitrophenylhydrazone lies at 148 to 149 °. Benzene can also be used as a solvent instead of chloroform.

Example 9

50.4 parts of 1,2-diphenyl-3,5-dioxopyrazolidine are suspended in 400 parts by volume of benzene, dropwise with stirring with 34.1 parts of p-methoxy-benzoyl chloride, dissolved in 35 parts by volume of benzene, added and the mixture heated to boiling for 5 minutes and then another 5 hours stirred further at room temperature. Then one sucks off the undissolved matter and works the benzene solution in the manner described in Example 5. 1,2-Diphenyl-4- (p-methoxy-benzoyl) -3,5-dioxopyrazolidine melts after recrystallization from alcohol at 162 to 163 °. It can also be produced by means of Pyridine can be used as a condensing agent analogously to Example 5.

Example 10

A solution of 14.1 parts of benzoyl chloride in 15 parts by volume of benzene becomes a suspension with stirring of 25.2 parts of 1,2-diphenyl-3,5-dioxopyrazolidine and 27.6 parts of anhydrous potassium carbonate in 200 parts by volume Benzene was added dropwise and the reaction mixture was refluxed for about 4 hours. After cooling down is filtered, the benzoin solution washed with 2N hydrochloric acid and water and evaporated. The residue is worked up as in Example 8, the first sodium bicarbonate extract being replaced by unreacted 1,2-diphenyl-3,5-dioxopyrazolidine can be contaminated. The product obtained is the same as that described in Example 8 identical.

Example 11

To 25.2 parts of 1,2-diphenyl-3,5-dioxopyrazolidine, suspended in 200 parts by volume of benzene and 35 parts by volume Pyridine, 13.7 parts of acetoxyacetyl chloride, dissolved in 15 parts by volume of benzene, are added dropwise with stirring and stirred for about 14 hours at room temperature. Then the reaction mixture is filtered and the precipitate, that from a pyridine compound of 1,2-diphenyl-4- (a-acetoxyacetyl) -3,5-dioxopyrazolidine consists, purified by recrystallization from alcohol. The crystallized pyridine compound melts at 164 to 172 ° with decomposition. The free 1,2-diphenyl-4- (ct-acetoxyacetyl) -3,5-dioxopyrazolidine can be obtained therefrom by decomposition with 2N hydrochloric acid with the addition of 10% alcohol and stirring. The one left behind pyridine-free substance melts at 117 to 118 °.

Claims (2)

Patent claims: 1. Process for the preparation of therapeutically effective, 4-substituted 1,2-diphenyl-3,5-dioxopyrazolidines the general formula CO-N-Ar ₁
R -CO-CH / I XO-N-Ar ₂ or their tautomeric forms, in which R denotes an aliphatic, aromatic, araliphatic or cycloaliphatic hydrocarbon radical which can be interrupted by —CO - O— and in which an aromatic hydrocarbon radical can be substituted by hydroxyl or low molecular weight alkoxy groups, and Ar ₁ and Ar ₂ Phenyl radicals which can be substituted by low molecular weight alkyl or hydroxyl groups, characterized in that a reactive, functional derivative of a carboxylic acid of the general formula is used R -COOH or the free carboxylic acid on a 1,2-diphenyl-3,5-dioxopyrazolidine the general formula / CO-N-Ar ₁ CH ₉ III XO-N-Ar ₉ or the general formula CO-N-Ar ₁ ' IV XO - Ar, wherein Ar ₁ 'is an aralkyloxyphenyl radical, and Ar ₁ , Ar ₂ and R have the meaning defined above, optionally in the presence of a basic condensing agent, allowed to act and, if reacted with a compound of the formula IV, the condensation product is hydrogenolyzed by means of catalytically activated hydrogen. 2. The method according to claim 1, characterized in that the basic condensation agent Pyridine used. Considered publications:
German Patent Nos. 903 578, 407 487;
Chem. Ber., 88 (1955), pp. 1353-1360. © 009 508/599 4.60