CS212286B2 - Method of making the molecular compound of betha-diethylaminothylamide of the p- chlorphenoxyvinegar acid with the 4-n-butyl-3,5-diketo-1,2-diphenylpyrazolidine - Google Patents

Abstract

By reacting together p- chlorophenoxyacetic acid, beta - diethylaminoethylamine and 4-n- butyl-3,5-diketo-1,2-diphenyl- pyrazolidine in the medium of a non- polar solvent at the temperature of 107 to 148 DEG C, the molecular compound of these three reactants is obtained in a single reaction, the said compound having the Formula 1 <IMAGE> The molecular compound is isolated from the reaction medium and purified by crystallisation from an organic water-miscible polar solvent containing not less than two moles of water per mole of the molecular compound. The molecular compound produced by the process according to the invention has antiphlogistic and antirheumatic properties.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a process for the preparation of a p-chlorophenoxyacetic acid beta-diethylaminoethylamide molecular compound with 4-n-butyl-3,5-diketo-1,2-diphenylpyrazolidine of the formula I

Cl

2 ^H 5 O-CH 3 -CONHCHo-CHo-NH

AND

C ₂ H

(AND)

P-Chlorophenoxyacetic acid beta-diethylaminoethyl amide II is commonly used for medical purposes

(II) and 4-n-butyl-3,5-dlketo-1,2-diphenylpyrazolidine of formula III

(III)

The compounds of formula II and III and the molecular compound of formula I are used as anti-inflammatory and anti-rheumatic agents, wherein the molecular compound beta-diethylaminoethylamide of p-chlorophenoxyacetic acid with 4-n-butyl-3,5-diketo-1,2-diphenylpyrazolidine has a lower acute toxicity compared to the use of 4-n-butyl-3,5-diketo-1,2-diphenylpyrazolidine.

Polish patent No. 60 210 discloses a process for the preparation of the p-chlorophenoxyacetic acid beta-diethylaminoethylamide molecular compound with 4-n-butyl-3,5-diketo-1,2-diphenylpyrazolidine, comprising 4-n-butyl- 3,5-diketo-1,2-diphenylpyrazolidine reacted with a beta-diethylaminoethylamide of p-chlorophenoxyacetic acid in equimolar amount with the ^running ma u rea tion ^to and / or ^P r hu ^Ube collation must ^b e ^{t argue} in omna ^d and ^d ales množst.v ^p ^ he ekvtao rním in proportion to the resulting product. The beta-diethylaminoethylamide of p-chlorophenoxyacetic acid, which is used to produce the molecular compound with 4-n-butyl-3,5-diketo-1,2-diphenylpyrazolidine, can be obtained as described in the literature. The process is carried out by chlorinating p-chlorophenoxyacetic acid with thionyl chloride or another suitable chlorinating agent and the acid chloride obtained is condensed with beta-diethylaminoethylamine as described in British Patent No. 942,761 or with beta-hydroxyethylamine as described in U.S. Pat. GDR of Patent No. 92,727.

The method described in British Patent No. 942,761 provides p-chloro-phenoxyacetic acid beta-diethylaminoethylamide by condensation with beta-diethylaminoethylamine acid chloride, while the process described in GDR No. 92,727 yields p- hydroxyethylamide p- chlorophenoxyacetic acid, the hydroxyl group of which can then be replaced with chlorine by the action of thionyl chloride, and the p-chlorophenoxyacetic acid beta-chloroethylamide thus obtained is condensed with diethylamine. This reaction results in the desired 3-diethylaminoethylamide of p-chlorophenoxyacetic acid.

During the action of diethylamine on beta-chloroethylamide beta-chlorophenoxyacetic acid

212286 also forms 2- (p-chlorophenoxymethyl) oxezoline Δ ² , which contaminates the resulting product. Isolation of the desired β-chloro-phenoxyacetic acid beta-diethylaminoethyl amide while removing the above product is accomplished by coupling the β-chloro-phenoxyacetic acid beta-diethyl aminoethyl amide to 4-n-butyl-3,5-diketl-1,2-diphenylpyrazolidine.

In the following, Scheme I illustrates a process for the preparation of the p-chlorophenoxyacetic acid beta-diethylminoethylamide compound with 4-n-butyl-3,5-diketo-1,2-dipheylpyrazoloidine of formula I in a known manner.

-CH ₂ -COOH

(c ₂ h ₅ ) ₂ nch ₂ ch ₂ nh ₂ \ / (c ₂ h ₅ I ₂ nch ₂ ch ₂ nh ₂

-ch ₂ -con ₂ -ch ₂ -n

CpH,

. 2H ₂ O n - _{C 4} H ₉

Disadvantages of the known method for producing a beta-diethylaminoethylamide of p-chlorophenoxyacetic acid and its molecular compounds are 4-n-butyl-3,5-diketo-1,2-pyrazolidine consist in the fact that it is not ^for the ^{lik t} and ^p upnový ratchet pos u ^{t p, PRICE} EMZ is necessary to use n ^¹H chl.ora ^No such agents to ^{the example,} thionyl chloride, which is disadvantageous when the process on an industrial scale.

The above disadvantages of the known process can be overcome by the process according to the invention.

There is no mention in the literature that p-chloro-phenoxyacetic acid beta-diethylaminoethylamide can be obtained by direct action of beta-diethylaminoethylamine on p-chloro-phenoxyacetic acid, although a method for obtaining other amides in a similar manner is known.

It is possible to obtain p-chlorophenoxyacetic acid beta-diethylaminoethylamide by heating p-chlorophenoxyacetic acid with an excess of beta-diethylaminoethylamine in a non-polar solvent such as toluene. the p-chlorophenoxyacetic acid beta-diethylaminoethylamide thus obtained is, however, strongly colored. Also, the 4-n-butyl-3,5-diketo-1,2-diphenylpyrazolidine molecular compound obtained by the process of Polish Patent No. 60,210 has an off-yellow color which cannot be removed by conventional methods, for example by crystallization. This nepMznťvý bui ^l e ^d e is ^the DTA-DTG nes OSH ^ z ^ tan ^ o ^ am u Neto! ^{in the} amide, tar compounds are formed and formed.

It has now been unexpectedly found that when 4-n-butyl-3,5-diketo-1,2-diphenylpyrazolidine binds to the p-chloro-phenoxyacetic acid beta-diethylaminoethylamide at birth at amidation which is carried out at a temperature of 107 to 148 ° C, beta-diethylaminoethylamide of p-chlorophenoxyacetic acid is protected against heat decomposition, as its resistance to elevated temperature increases as a molecular compound is formed.

Accordingly, the present invention is based on the fact that the molecular compound beta-diethylaminoethylamide of p-chlorophenoxyacetic acid with 4-n-butyl-3,5-diketo-1,2-diphenylpyrazolidine is obtained during the direct amidation of p-chlorophenoxyacetic acid with beta- diethylaminoethylamine in the presence of 4-n-butyl-3,5-diketo-1,2-diphenylpyrazolidine in a non-polar organic solvent at a temperature of 107-148 ° C as shown in the following Scheme II.

Cl

-r

Сн Cl ₂ - CONHCH ₂ - CH ₂ - NH

2H ₂ O

The amidation of p-chlorophenoxyacetic acid according to the invention is carried out using a stoichiometric amount of p-chlorophenoxyacetic acid and 4-n-butyl-3,5-diketo-1,2-diphenylpyrazolidine, while beta-diethylaminoethylamine can be used in stoichiometric amounts or , 7% excess.

The reaction medium is a non-polar organic solvent, preferably toluene or xylene.

The water resulting from the amidation binds to the molecular amide compound with 4-n-butyl-3,5-diketo-1,2-diphenylpyrazolidine. After cooling the reaction mixture to 10 ° C to 20 ° C, the resulting molecular compound crystallizes from the reaction medium with 1 molecule of water. When most of the water is removed by evaporation, an oily product is formed upon cooling, which can also be obtained by distilling off the solvent.

The crude product obtained in the form of hydrated crystals or in the form of an oily yellow liquid is only slightly contaminated with tarry substances. Crystallization from an organic polar water-miscible solvent containing a certain amount of water yields crystals of a dihydrated molecular compound of high purity, the resulting product being suitable for medical use.

Of the organic polar water-miscible solvents, acetone or ethanol containing at least 2 moles of water per mole of molecular compound is preferred.

The p-chlorophenoxyacetic acid beta-diethylaminoethylamide molecular compound with 4-n-butyl-3,5-diketo-1,2-diphenyl-pyrazole-dione binds one or two molecules of water so strongly that complete dehydration can only occur at temperatures corresponding to boiling point of xylene. Thus, the molecular compound to be formed can be used as a water binding agent resulting from the breakfast.

The effect of the protective effect of 4-n-butyl-3,5-deceto-1,2-lefenylpyrazolidine on the decomposition of p-chloro-phenoxyacetic acid beta-diethylaminoethylamil at a higher temperature can be demonstrated by heating a sample of p-chloro-phenoxyacetic acid beta-diethylaminoethylamil and of the same amide with 4-n-butyl-3,5-diketo-1,2-lifenylpyrazolidine at 120 ° C for 3 hours. The ethanolic solutions of these samples absorb very different visible light, indicating a different degree of degradation of both samples and different levels of color contamination, which is very high in the case of amide and only marginally in the case of amide with 4-n-butyl-3. 5-deceto-1,2-diphenylpyrazolidine.

An advantage of the process according to the invention is to obtain the molecular compound beta-diethylaminoethylamide of p-chlorophenoxyacetic acid with 4-n-butyl-3,5-diketo-1,2-diphenylpyrazoliline in a single step by direct reaction of p-chlorophenoxyacetic acid, beta-deethylaminoethylamine and 4- n-butyl-3,5-liketo-1,2-defenylparazolidine. Recrystallization from hydrated acetone or a similar solvent yields a high purity product suitable for medical use.

The invention will be illustrated by the following examples.

Example 1

To 200 ml of toluene are added 77 g of 4-n-butyl-3,5-deceto-1,2-defenylpyrazolidine, 46.5 g of p-chlorophenoxyacetic acid and 29 g of beta-diethylamenoethylamine, and the mixture is heated to boiling point below. reflux condenser. The mixture was boiled for 8 hours and then cooled to 20 ° C. Crystals of p-chlorophenoxyacetic acid beta-diethylamenoethylamide monohydrate compound with 4-n-butyl-3,5-diketo-1,2-diphenylpyrazolidene are precipitated.

After filtration and washing with toluene, the crystals were mixed at ⁶⁰ ° C with 80% aqueous acetone, to which 252 g of crystals were added. After cooling, the molecular compound beta-diethylaminoethylamide of p-chlorophenoxyacetic acid with 4-n-butyl-3,5-diketo-1,2-diphenyl-pyrazolidine crystallizes with 2 molecules of water, which is collected by filtration, washed with aqueous acetone solution and dried. at 60 ° C.

102 g of a molecular compound are thus obtained in a yield of 65%.

The p-chlorophenoxyacetic acid beta-diethylaminoethylamide molecular compound with 4-n-butyl-3,5-diketo-1,2-diphenylpyrazolidine is a white powder readily soluble in methanol, dimethylformamide, dioxane, acetone and ethanol. The solubility of chloroform is 0.5 g / 10 ml. It is insoluble in water, ether, benzene and toluene. Melting point: 89-90 ° C.

A 0.002% solution of the molecular compound in methyl alcohol has a maximum absorption of ultraviolet light in the region of 225 to 270, a minimum absorption at 239 / am.

Example 2 '

77 g of 4-n-butyl-3,5-diketo-1,2-diphenylpyrazolidine, 46.5 g of p-chlorophenoxyacetic acid and 30.5 g of beta-diethylaminoethylamine are dissolved in 200 ml of toluene and the mixture is heated to a reflux condenser in a flask which is still provided with a device for absorbing water. The mixture was boiled for 8 hours, during which time approximately 2.5 ml of water was removed. Thereafter, toluene was completely distilled off and the oily residue was treated at 60 ° C with 80% acetone in water to give 252 g of compound. Upon cooling, the p-chlorophenoxyacetic acid beta-diethylaminoethylamide molecular compound crystallizes with 4-n-butyl-3,5-diketo-1,2-diphenylpyrazolidine with 2 water molecules. This product was collected by filtration, washed with aqueous acetone, and dried at 60 ° C.

In this way 108.5 g of a molecular compound having the properties given in Example 1 are obtained in a yield of 69%.

Example 3

77 g of 4-n-butyl-3,5-diketo-1,2-diphenylpyrazolidine, 46.5 g of p-chlorophenoxyacetic acid and 29 g of beta-diethylaminoethylamine are dissolved in 220 ml of xylene and the mixture is heated to reflux. cooler for a total of 4 hours.

After the OM ^{t b b} SAH An ^alkyl zc ^{hl DI} at 20 ° C. From the reaction mixture ^and fattening ^y S ^{t where} We observe mcnohydrát beta-diethylaminoethylamide of p-chlorophenoxyacetic with 4-n-butyl-3,5-diketo-1,2-diphenylpyrazolidine.

The resulting product was collected by filtration and washed with xylene, and then the crystals were mixed at 80 ° C with 80% aqueous acetone, using 252 g of crystals. After cooling, a molecular compound as crystals with two molecules of water, the product was collected by filtration, washed with a ^d Nym mites ^to em acetone and drying ^Si, p ^r i te ^pl of ^T e ⁶⁰ ° C.

In this way, 104 g of a molecular compound having the properties given in Example 1 are obtained in a yield of 66%.

Example 4

77 g of 4-n-butyl-3,5-diketo-1,2-diphenylpyrazolidine _} 46.5 g of p-chlorophenoxyacetic acid and 31 g of beta-diethylaminoethylamine are dissolved in 220 ml of xylene, and the mixture is heated to reflux. a condenser in a flask fitted with a device for absorbing water. The mixture was boiled for 4 hours, during which time 3.8 ml of water was removed and the boiling point of the liquid rose to 148 ° C.

After cooling the reaction mixture to 20 ° C, the title compound is obtained as an oil; Which, after separation from the xylene layer, is mixed with an 80% aqueous acetone solution. 265 g of an oily liquid are used and the mixture is heated to 60 ° C.

The p-chlorophenoxyacetic acid beta-diethylaminoethylamide molecular compound crystallizes with 4-n-butyl-3,5-diketo-1,2-diphenylpyrazolidine, which contains 2 molecules of water. The resulting product was collected by filtration, washed with aqueous acetone, and dried at 60 ° C.

In this way, 114 g of a molecular compound having the properties given in Example 1 are obtained in a yield of 72%.

SUBJECT OF THE INVENTION

Claims (1)

A process for the preparation of the molecular compound beta-diethylaminoethylamide of p-chlorophenoxyacetic acid with 4-n-butyl-3,5-diketo-1,2-diphenylpyrazolidine, comprising reacting p-chlorophenoxyacetic acid in the presence of 4-n-butyl -3,5-diketo-1,2-diphenylpyrazolidine with beta-diethylsminoethylamine, which is used in a stoichiometric amount or in up to 7% excess in a nonpolar solvent at a temperature of 107 to 148 ° C, the obtained molecular compound is isolated and purified by crystallization from organic , water-miscible polar maiden name Oust ^p and ^{1 dl} of ^the now obsolete and ^{L b} exceed ESPO ^N2 mo ^ly water to 1 ^L mo molebrulární merged-ny.