NO151816B - TRAFFIC CONTAINER - Google Patents

Abstract

1. A stackable container (1) which has been erected from a blank and which has a quadrilateral container floor (2) which is surrounded on all sides by an upwardly conically opening container wall which, in its corner regions, has triangular fold portions (8-14) which extend from the corners (7) of the container floor (2) and which, partly over themselves and partly over quadrilateral wall regions (3, 4, 5, 6) disposed therebetween, form transitional portions between these wall regions which are folded so as to comprise three layers of material, characterized in that seven fold portions (8-14) are provided in each corner region, adjacent fold margins (17, 21 ; 20, 24 ; 23, 27) being contiguous, and in that the container (1) has a capacity of at least 56 litres.

Description

Process for the production of 3,5-disubstituted isoxazole derivatives with therapeutic effect.

The present invention relates to a further process for the production of frenistiligerous 3,5-disubstituted fatty acids

isoksåzdlderivatéf sbhi generally exhibits^ for-skjélligé pharmacological åkvitétér sbni f: e.g.

aritipyretic, arialgeic, arititussive bg/eliér anti-inflammatory activity.

The invention thus resulted in a freni-gahg method for the production of 3,5-disubstituted té

isbksåzoideriVatér with therapeutic effect and

with a general formula I

where R is an unsubstituted or a lower alkoxy or halogen substituted phenyl radical or a pyridyl radical, R' bg R" is each a hydrbgéh-åtbiri or an iåVere alkyl group, respectively" represents éri piperidinb-; pyffbiidih'6- or morph oliftbgriippe, and Å is one lower alkylene group, bg salts thereof, bi the particularity of the process according to tii invention ef åt åmihbaikyfi with therein general formula li in which R!, R" bg A liver liar Ben above-mentioned meaning, converted niéd et riitrilbksyd niea formula lii

where R has the above-mentioned meaning, and the compounds obtained are optionally transferred in a known manner in a salt.

The one starting material for the present invention, namely the aminoalkyne of formula (II) can be prepared by methods known per se, e.g. by reacting an amino alkyl halide with the formula:

wherein X is a halogen atom (eg chlorine or bromine) and R' and R" and A each have the above meaning, with an alkali metal acetylide [Campbell et al.: J. Org. Chem., Vol. 17, p. 1141 (1952); Epsztein et al.: Bull. Soc Chim. France p. 952

(1953)]. The second starting material of the present invention, namely the nitrile oxide (III) can be prepared from the corresponding aldehyde according to the following reaction core:

wherein X' is a. halogen atom (e.g. chlorine or bromine) and R has the above meaning.

According to the present invention, the reaction between the aminoalkyne (II) and the nitrile oxide of formula (III) can be carried out in an inert solvent at a wide temperature range from room temperature to reflux temperature. As an inert solvent, it can e.g. alkanols (e.g. methanol, ethanol), haloalkanes (e.g. chloroform, carbon tetrachloride), benzene, toluene, xylene, ether, tetrahydrofuran and dioxane are used. Of these solvents, it is preferred to use a non-polar solvent, such as e.g. benzene, ether and tetrahydrofuran. The nitrile oxide of formula (III) is largely unstable and must therefore be used in freshly prepared form. In accordance with . with this, the method can be carried out by e.g. adding the aminoalkyne of formula (II) to the reaction mixture of the hydroxamyl halide (C) and an alkaline reacting substance in the aforementioned inert solvent in which the produced nitrile oxide of formula (III) is present. The procedure can alternatively be advantageously carried out by e.g. to add an alkaline reacting compound to an already prepared mixture - of the aminoalkyne of formula (II) and the hydroxyamyl halide (C) in the aforementioned inert solvent whereby the produced nitrile oxide of formula (III) instantly reacts with the aminoalkyne of formula (II). Examples of the alkaline compound used as the acid eliminating agent in these operations are alkali metal or alkaline earth metal hydroxides

(e.g. sodium hydroxide, potassium hydroxide,

calcium hydroxide, alkali metal or alkaline earth metal salts of inorganic or organic weak acids (e.g. sodium carbonate, potassium carbonate, sodium bicarbonate, sodium acetate), ammonia and amines (e.g. dimethylamine, pyridine, picoline, dimethylaniline). Instead of those mentioned

alkaline-reacting compounds, the aminoalkyne of formula (II) itself can be used as the acid-eliminating agent.

The thus produced isoxazole compounds (I) are liquid or solid in the free state. In order to

ease of preparation, these can be converted into their acid addition salts or quaternary salts, e.g. by treating the base with an acid such as hydrogen chloride, hydrogen bromide, hydrogen] odide, sulfuric acid, nitric acid, phosphoric acid, thiocyanic acid,

carbonic acid, acetic acid, propionic acid, oxalic acid,

citric acid, tartaric acid, succinic acid, salicylic acid, benzoic acid or palmitic acid or a quaternizing agent such as e.g. methyl chloride, ethyl chloride, ethyl bromide, methyl iodide, ethyl iodide, phenethyl bromide, jensenesulfonyl chloride, benzenesulfonyl bromide, or p<1>toluenesulfonyl bromide in a suitable solvent such as e.g. water, methanol, ethanol, ether, benzene and toluene.

The isoxazole compounds of formula (I) and non-toxic salts thereof are useful as antipyretic, analgesic, antitussive and/or anti-inflammatory agents. Generally speaking, these compounds exhibit a variety of pharmacological actions associated with low toxicity. 1 The following examples represent preferred embodiments of the invention.

Example 1:

To a solution of 4-dimethylamino-1-butyne (0.97 g) in triethylamine (3.4 g), a solution of benzohydroxaamyl chloride (1.6 g) in benzene (10 ml) is added at 5° C. with stirring, and the resulting mixture is gradually heated to 60 to 70°C and then stirred for 1 hour. After cooling, the reaction mixture is shaken out with dilute hydrochloric acid. The aqueous phase is washed with benzene, made alkaline with 20% sodium hydroxide solution and shaken with ether. The ether layer is washed with water, dried over dry potassium carbonate and the solvent is removed by distillation. The resulting liquid is distilled under reduced pressure to give 3-phenyl-5-(2-dimethylamino-ethyl)-isoxazole (0.83 g) as a pale yellow oil boiling at 151°C/4 mmHg. The hydrogen chloride is colorless needles which melt at 187-188° C when crystallized from ethanol.

Example 2:

To a benzene solution of benzonitrile oxide prepared by reacting benzohydroxaamyl chloride (1.6 g) with triethylamine (3.4 g) in benzene (10 ml) at 5° C. is added 4-dimethylamino-1-butyne (0.97 g ) and the resulting mixture is gradually heated to 60-70° C and then stirred for one hour. The reaction mixture is treated as in Example 1 to give 3-phenyl-5-(2-dimethylaminoethyl).-isoxazole (0.79 g) as a pale yellow oil boiling at 151° C./4 mm Hg.

Example 3:

To a solution of 5-piperidino-1-pentyne (3.0 g) and triethylamine (11.1 g) in benzene (40 ml), is added dropwise a solution of benzohydroxaamyl chloride prepared from benzaldehyde roxime (12.1 g) in benzene ( 30 ml) at 10-15° C with stirring, and the resulting mixture is stirred for 1 hour at 60-70° C. After cooling, the reaction mixture is filtered. The filtrate is shaken out with 5% hydrochloric acid. The aqueous layer is made alkaline with 20% sodium hydroxide solution and shaken with ether. The ether layer is washed with water, dried over anhydrous potassium carbonate and concentrated to give a crude product of 3-phenyl-5-(3-piperidinopropyl)-isoxazole (3.6 g) as a yellowish oil. The hydrochloride is colorless plates melting at 166-167° C, when crystallized from acetone.

Example 4:

To a solution of 4-morpholino-l-butyne (1.4 g) and triethylamine (1.0 g) in benzene (20 ml), is added dropwise a solution of p-methoxy-benzohydroxaamyl chloride (930 mg) in benzene (10 ml) at 10-12°C, and the resulting mixture is heated to 55-60°C and stirred for 1 hour. After cooling, the reaction mixture is filtered. The filtrate is shaken with dilute hydrochloric acid. The aqueous phase is washed with benzene, made alkaline with 20% sodium hydroxide solution and cooled with ice. The precipitated crystals are collected by filtration, washed with water, dried and recrystallized from petroleum ether to give 3-p-methoxyphenyl-5-(2-morpholinoethyl)isoxazole (1.1 g) as colorless needles melting at 106-107 ° C. The hydrochloride is colorless needles melting at 222—224° C, when crystallized from ethanol.

Example 5:

To a suspension of p-methoxybenzohydroxyamyl chloride (930 mg) is added dropwise 14% sodium hydroxide solution (10 ml) at 0° C. with stirring, and the resulting mixture is stirred for 30 min. at — 2 — 0° C. The resulting mixture is shaken with ether. The ether layer is washed with water and dried over anhydrous potassium carbonate. The dried ether solution of p-methoxy-benzonitrile oxide is added dropwise to a solution of 4-morpholino-1-butyne (1.4 g) in ether (10 ml) at 0-2° C. and then refluxed for 1 hour. The reaction mixture treated as in Example 4 to give 3-p-methoxy-cyphenyl-5-(2-morpholinomethyl)-isoxazole (181 mg) as crystals melting at 106-107°C.

Example 6:

To a solution of p-methoxybenzohyroxamyl chloride (1.9 g) in benzene (19 mL) is added a mixture of triethylamine (1.0 g) and benzene (5 mL) with stirring, and the resulting mixture is stirred for 15 minutes at 5° C. The resulting benzene solution of p-methoxy-benzonitrile oxide is added dropwise to a solution of 4-piperidino-1-butyne (2.7 g) in benzene (10 ml) at 5° C and the resulting mixture stirred for 1 hour at 60° C. The reaction mixture is treated as in Example 4 to give 3-p-methoxy-phenyl-5-(2-piperidinoethyl)-isoxazole (1.37 g) as colorless plates melting at 68-69 ° C. The hydrochloride crystallizes in colorless prisms which melt at 217-218° C, when crystallized from ethanol.

Example 7:

To a mixture of 3-piperidino-1-propyne (1.9 g) triethylamine (1.9 g) and benzene (23 ml) is added dropwise a solution of 3-chlorobenzo-hydroxaamyl chloride (2.2 g) in benzene (16 ml) at 5° C with stirring and the resulting mixture is stirred for 1 hour at 70° C. The reaction mixture is combined with 6 N hydrochloric acid for acidification and shaken vigorously. The precipitated crystals are collected by filtration and recrystallized from ethanol to give 3-(p-chlorophenyl)-5-piperidinomethylisoxazole hydrochloride (1.7 g) as colorless needles melting at 245.5-247°C.

Example 8:

To a solution of 4-dimethylamino-1-butyne (1.9 g) and triethylamine (3.0 g) in ethanol (15 ml), 2-pyridylhydroxaamyl chloride (1.95 g) is added at 10-12° C with stirring and the resulting mixture is stirred for 2 hours at 60-65° C. The reaction mixture is concentrated under reduced pressure, combined with a small amount of water and shaken with chloroform. The chloroform layer is dried over anhydrous potassium carbonate, treated with activated carbon and the solvent is removed by distillation under reduced pressure. The resulting liquid is combined with petroleum ether and allowed to stand for crystals to separate. After separation of the crystals by filtration, the filtrate is concentrated and distilled under reduced pressure to give 3-(2-pyridyl)-5-(2-methylaminoethyl)-isoxazole

(1.8 g) as a pale yellow oil boiling at 127° C/2 mm Hg. The citrate crystallizes from ethanol in colorless prisms which melt at 110-111° C.

Other isoxazole compounds are prepared in a similar way. Some examples of these and also other isoxazole compounds that have been prepared are shown in the following table:

Claims (1)

Trough-shaped container (1) formed from a single blank and with a square container base (2) which is surrounded on all sides by an upwardly conical extended container wall which in its corner areas has triangular folding parts (8-14) that extend from the container base corners (7) and together, respectively together with intermediate square wall panels (3, 4, 5, 6), in three layers of material form folded transitions between these wall panels, characterized by the fact that in each corner area seven folding parts (8-14) are arranged, and that adjacent folding edges (17, 21; 20, 24; 23, 27) touch each other.