NO151704B - PROCESS OF PREPARING ACID ADDITION SALTS OF 3,4-DIACYLOXY-ALFA - ((METHYLAMINO) -METHYL) -BENZYL ALCOHOL - Google Patents

Abstract

New process for the preparation and isolation of 3,4-diacyloxy-α - [(methylamino) -methyl] -benzyl alcohol of formula. wherein R represents alkyl or aralkyl, as its acid addition salt, preferably as its hydrochloride. According to the invention, an acid addition salt of the compound of formula I and containing a keto group in its α-position is reduced by means of an alkali metal borohydride in an acidic solvent, water is added to the reaction mixture and the desired reaction product is extracted into a chlorinated hydrocarbon.

Description

Process for the preparation of new therapeutically effective 1,2-diaryl-4-alkyl-3,5-dioxo-pyrazolidines.

The present invention relates to hitherto unknown derivatives of 1,2-diphenyl-3,5-dioxo-pyrazolidine with valuable pharmacological properties. 1,2-diphenyl-3,5-dioxo-4-n-butyl-pyrazolidine (phenyl-butazone) as a medicine has achieved great therapeutic importance, especially for the treatment of acute and chronic inflammatory diseases.

It has now been found that 4-substituted 1,2-diaryl-3,5-dioxo-pyrazolidines of the general formula I

in which R means an alkyl residue with a maximum of 3 carbon atoms and n is equal to 2-4

and their salts, with inorganic and organic bases likewise have valuable anti-phlogistic properties. The compounds with the general formula I, such as e.g. The 1-(m-tolyl)-2-(p-hydroxy-phenyl)-4-n-butyl-3,5-dioxo-pyrazolidine differs advantageously in terms of the side effects from the like

connections. They are distinguished by a high healing intensity, which allows a significant reduction of the applied dose, and causes a lower load on the organism with foreign substances as well as after the parenteral, especially the nitro-nuscular administration. On that in acid-lor search (rats) by sulfonamide-diuretica-stimulated electrolyte excretion, the aforementioned 1-(m-tolyl)-2-(p-hydroxy-:enyl)-4-n-butyl-3,5- dioxo-pyrazolidine in-*an inhibitory influence. Furthermore, the strong biosynthesis inhibition of sulfated polysaccharides such as chondroitin-sulphuric acid in the granulation tissue is also highlighted experimentally in animals.

The hitherto unknown compounds with the general formula I are suitable, e.g. for the treatment of rheumatic diseases, whereby they can be administered per os or rec-fcal or in the form of aqueous solutions of lere's salts, also parenterally, e.g. intramuscularly or intravenously.

In the general formula I mentioned above, the substituent in the 4-position in the pyrazole ring, corresponding to the meaning of n, is an ethyl, n-propyl, n-butyl or n-pentyl residue. R is sn methylethyl, n-propyl or isopropyl residue.

The compounds of the general formula I are prepared by treating the compounds of the general formula II,

real

in which R, is an arylmethyl or diarylmethyl residue and R and n have the meanings given above, with catalytically activated hydrogen until the absorption of the substantially equimolar amount of hydrogen, or by subjecting a compound of the general formula III

in which R 2 means an acyl residue or an α-alkoxy alkyl residue, whereby the alkyl residue of the alkoxy substituent can be ring-shaped with the main chain of a tetrahydro-pyranyl residue, and R and n have the above meaning, a solvolysis. The obtained compound of the general formula I is transferred, if desired, to a salt with an inorganic or organic base.

The starting materials with the general formula II, in which R preferably means the benzyl or benzhydryl residue, are hydrated in alkaline-aqueous solution or in an inert organic solvent such as e.g. ethanol in the presence of Raney nickel, or a noble metal catalyst such as palladium on charcoal. The effect of hydrogen can be carried out at room temperature and atmospheric pressure until the recording stops. Under energetic conditions, the hydrogenation may have to be interrupted after the uptake of the theoretical, equimolar amount of hydrogen to prevent side reactions.

For the solvolysis of the starting materials with the general formula III where R 2 means an α-alkoxy alkyl residue, e.g. a methoxy-methyl residue, α-methoxy-ethyl residue, α-ethoxy-ethyl residue, α-n-butoxy-ethyl residue or tetra-hydropyranyl-2-residue, are suitable, e.g. diluted hydrochloric acid in methanol at a moderately elevated temperature or up to boiling temperature.

The splitting off of an α-alkoxy alkyl residue R, can further take place, e.g. by treatment with methanol or another lower alkanol in the presence of an acidic catalyst such as sulfuric acid, p-toluenesulfonic acid or the acidic phosphoric acid and polyphosphoric acid ester mixture that occurs when phosphorus pentoxide is added to alkanol, or a Lewis acid such as e.g. aluminum chloride or boron trifluoride, at room temperature or at a moderately elevated temperature.

For hydrolysis of the starting materials with an acrylic residue, in particular an acetyl residue R,, can e.g. diluted caustic soda at a moderately elevated temperature or until boiling temperature is used. Under water-free conditions, an acyl residue R, can be split off, e.g. by treating a corresponding compound of the general formula III with methanolic ammonia solution.

The starting materials with the general formulas II and III can be prepared by various similar methods.

The starting materials with the general formulas can e.g. is produced by condensation of malonic acids with the general formula IV

where n has the meaning given above, with hydrazobenzene derivatives of the general formulas V, VI or VII

in which K, means an α-alkoxy alkyl residue, whereby the alkyl residue of the alkoxy substituent can be ring-shaped connected to the parent chain, and R 2" means an acyl residue and R and Rj have the meaning indicated above, in the presence of N,N'-disubstituted carbodiimides, in particular

division N,N'-dicyclohexylcarbodiimide in dioxane solution, as well as by condensation of dihalides of the malonic acids with the general formula IV with hydrazobenzene derivatives with the general formulas V and VII in the presence of an acid-binding agent, e.g. tertiary organic bases such as pyridine, dimethylamiline, triethylamine or tributylamine in the presence or absence of an additional organic solvent such as chloroform, diethylether or diisopropylether at room temperature or up to the boiling temperature of the reaction mixture.

The starting materials with the general formula II as well as part of the starting materials with the general formula III can be further prepared by condensation of dialkyl esters of malonic acid with the general formula IV with hydrazobenzene derivatives with the general formulas V or VI in the presence of an alkaline condensing agent, or by condensation of the alkyl ester halides of malonic acids of the general formula IV with hydrazobenzene derivatives of the general formulas V or VI in the presence of an acid-binding agent and treatment of the immediately obtained reaction product with alkaline condensing agents. The condensation of the malonic acid dialkyl esters with hydrazobenzene derivatives preferably takes place in organic solvents such as benzene, toluene, xylol, butanol or dibutyl ether at elevated temperatures, e.g. between 80°-160°, whereby the released alcohol is possibly continuously distilled off. Suitable alkaline condensation agents for this reaction are generally those which are able to replace a mobile hydrogen atom with a metal atom, e.g. alkali metals or their alcoholates, amides, hydrides and organometallic compounds, such as sodium, potassium, lithium, sodium ethylate, potassium ethylate, sodium amide, lithium hydride, phenyllithium and butyllithium. For the reaction of the alkyl ester halides with hydrazobenzene derivatives, the previously mentioned acid binding agents and then the previously mentioned alkaline condensing agents can be used. However, in this case the ring closure can already be completed under mild conditions, such as when using malonic acid dialkyl esters e.

Finally, it is also possible to prepare starting substances with the general formulas II and II by correspondingly introducing an n-alkyl residue with 2 to 4 carbon atoms in the 4-position in unsubstituted pyrazoline compounds according to methods known per se. For this purpose, one condenses e.g. corresponding 4-unsubstituted compounds with proprionaldehyde, butyraldehyde or valeraldehyde or corresponding unsaturated aldehydes such as crotonaldehyde e.g. by boiling in glacial acetic acid and by hydrogenating the obtained 4-alkylidene compounds respectively 4-alkenylidene compounds to starting materials with the general formulas II and III. This hydration of the semicyclic double bond and a possibly present extracyclic double bond can optionally be carried out simultaneously with the hydration. However, this introduction method for the 4-substituent is not limited to compounds with an arylmethyl or diarylmethyl residue R,.

The new compounds of the general formula I form relatively easily to easily soluble monobasic salts with the alkali hydroxides. Solutions of the same can be prepared by dissolving the new compounds in the calculated amount of alkali-lye, i.e. in solutions of lithium, sodium or potassium hydroxide. The new compounds also dissolve in alkali carbonate solutions.

The new compounds according to the invention respectively their alkali salts or salts with organic bases such as e.g. di-methylaminoethanol, diethylaminoethanol or piperazine can be converted into medicines by combination with suitable pharmaceutical carriers. The above-mentioned solutions of the alkali salts of the new compounds have a weak alkaline reaction and are well suited for injection. The drugs can also be capsules, powders, tablets and others for oral administration, suitable forms and can e.g. are produced by mixing active substances, i.e. the new 1,2-diaryl-4-alkyl-3,5-dioxo-pyralolidine with pharmaceutical carriers such as starch, milk sugar, stearic acid, talc, magnesium stearate etc. But they can also process des with semi-solid substances with a suitable melting range, e.g. cocoa butter, for suppositories.

The following examples explain in more detail the preparation of the new compounds. The temperatures are indicated in degrees Celsius.

Example 1.

a) 125 g sodium hydroxide is dissolved in 3 1 methanol. After adding 302 g of p-benzyloxy-m'-methyl-azobenzol (m.p. 81"), add 200 g of zinc dust in 5 equal portions during 30 minutes at reflux temperature in a nitrogen atmosphere and while stirring. Then stir the reaction mixture further for about 15 minutes, i.e. until

it doesn't stick in yellow anymore. Then felt-

the mixture is stirred and the filtrate is evaporated at 11 Torr to half the volume. The rest in-

contains the crude p-benzyloxy-m'-methyl-hydrazobenzene.

b) To the remainder obtained after a) to-

add 2000 ml of benzene and 1000 ml of water. It

organic phase is separated, dried over na-

trium sulfate and poured into a reaction vessel. An-

ter the distillation of approx. 1500 ml of benzene is added to one of 23 g and 400 ml of absolute ether

nol prepared sodium ethylate solution to which 216 g of n-butyl malonic acid diethyl ester has then been added and then emptied into 500 ml of xylol. The reaction mixture up-

is further heated at a bath temperature of

130°—140° for 12 hours with falling cooler,

whereby the solvent and released eth-

nol goes over. After cooling, the reaction mixture is stirred at 5° with 500 ml of ice water until a two-phase solution is present. The aqueous phase is shaken 2 more times, each time with 500 ml of ether and adjusted there-

after congo acid under vigorous stirring with hydrochloric acid. The crystals obtained are washed neutrally with water and recrystallized from ethanol. The 1-(m-tolyl)-2-(p-benzyloxy-phenyl-3,5-dioxo-4-n-butyl-pyrazolidine thus obtained melts at 120°C.

c) 96 g of 1-(m-tolyl)^2-(p-benzyloxy-phenyl)-4-n-butyl-3,5-dioxo-pyrazolidine

dissolve in a solution of 18 g of sodium

hydroxide in 500 ml of water and hydrate in approx.

weather of 30 g Raney nickel at room temperature

temperature and atmospheric pressure. After 9 hours, the hydrogen absorption comes to a standstill,

after it has reached approx. 93 percent of the theoretical. One filters from the catalyst,

shake the filtrate 2 times with ether and in-

henceforth it stands Congolese with concen-

triturated hydrochloric acid. The precipitated reaction product is taken up in ethyl acetate. After washing with water and thorough drying over sodium sul-

barrel, the ethyl acetate solution is evaporated in a vacuum and enough petroleum ether is added that no remaining clouding is possible. The 1-(m-tolyl)-2-(p-hydroxyphenyl)-3,5-dioxo-4-butyl-pyrazolidine crystallizes little by little. It melts at 113°.

Example 2.

25 g m-methyl-p'-acetoxy-hydrazoben-

zol is dissolved in a mixture of 17.6 g of pyridine and 200 ml of chloroform. At 0-5°, a solution of 19.7 g of n-butyl-malonic acid is added dropwise

dichloride in 100 ml of chloroform with stirring. The reaction mixture stands for 12 hours at room temperature and is then poured onto ice.

The organic phase is separated, shaken

0-5° with dilute hydrochloric acid and extracted

then 2 times each time with 500 ml sodium carbonate solution.

These extracts are set Congo sour, the

precipitated oil is dissolved in ethyl acetate and solvent

is dried with sodium sulfate and

pes at 11 Torr. The 1-(m-tolyl-2-(p-acetoxy-phenyl)-3,5-dioxo-4m-butyl-pyrazolidine is an oil, therefore it is hydrolyzed without

re cleaning. The remainder (approx. 30 g) is dissolved in 300

ml of 2-n caustic soda and heat for 30 minutes at 90-95°. The solution is filtered with charcoal and adjusted after it has been covered with 300 ml of ethyl acetate congo acid with concentrated hydrochloric acid. The organic phase is further worked up as described in example 1 to 1-(m-tolyl)-2-(p-hydroxyphenyl)-4-n-butyl-3,5-dioxo-pyrazolidine.

Example 3.

16 g of n-butyl-malonic acid are dissolved in 500 ml of absolute dioxane 30 g of m-methyl-p'-[tetra-hydropyranyl-(c()-oxy]-hydrazobenzene to

is added and 45 g of dicyclohexylcarbodiimide are added at once to the solution. The reaction mixture is left overnight at room temperature. The separated dicyclohexycarbamide is sucked off and the filtrate is evaporated at 11 Torr. The residue is dissolved in 1000 ml of ethyl

acetate and the solution is shaken twice with 500 ml l-n. sodium carbonate solution

nothing. These extracts are set with vinegar-

acid at pH 5 and the separated oil is dissolved in ethyl acetate. The obtained solution dry-

kes with sodium sulfate and evaporated at 11 Torr. The 1-(m-tolyl)-2-[p-(tetrahydro-pyranyl(cc)bxy-phenyl]-3,5-dioxo-4-n-

butyl-pyrazolidine cannot be crystallized, therefore it is hydrolysed directly. 4.2 g are dissolved in 84 ml methanol, 3.4 ml l-n. hydrochloric acid to

is set and the mixture is boiled for 30 minutes un-

where reflux. At room temperature to

add 8.4 ml of caustic soda and the mixture in

steamed at 11 Torr. The rest is distributed between

lom the ethyl acetate and water. The organic phase is dried over sodium sulfate and

pes. The 1-(m-tolyl)-2-(p-hydroxyphenyl)-3,5-dioxo-4-n-butyl-pyrazolidine recrystallized

lysed as described in example 1.

Prepared in an analogous manner: 1-(m-tolyl)-2-p-hydroxyphenyl)-3,5-dioxo-4-n-propyl-pyrazolidine m.p. 125° and 1-(m-tolyl)-2-(p-hydroxyphenyl)-3,5-

dioxo-4-n-amyl pyrazolidine m.p. 71°.

Claims (1)

Process for the preparation of new therapeutically effective 1,2-diaryl-4-alkyl-3,5-dioxo-pyrazolidines of the general formula I, in which R, means an arylmethyl or diarylmethyl residue and R and n above have an-; 335 5 given meaning, with catalytically activated hydrogen until the absorption of the substantially equimolar amount of hydrogen, or subject to a compound of the general formula III in which R 2 means an acyl residue or an α-alkoxy alkyl residue, where the alkyl residue of the alkoxy substituent may be cyclically connected to the parent chain, and R and n have the meaning indicated above, a solvolysis, and transfers the obtained compound of the general formula I, if desired, to a