DK149332B - DIHYDROQUINOLINE ALDEHYDE CONDENSATION PRODUCTS OR ACID ADDITION SALTS WITH ANTIOXIDATIVE EFFECT - Google Patents

Description

in 149332 o

The invention relates to novel non-toxic tri or tetramethyl-1,2-dihydroquinoline aldehyde condensation products or acid addition salts thereof having antioxidant activity.

The tri or tetramethyl-1,2-dihydroquinoline-aldehyde condensation products of the present invention are characterized in that they have a chemical structure similar to the general formula 10? H3 r1 Γ nj ch3 H3C H L g ch3.

N represents a hydrogen atom or an alkyl group of 1-4 carbon atoms, R 1 represents a hydrogen atom or a methyl group bonded to any substitutable carbon atom except that at the 6-position, n means 1, 2 or 3, but advantageously in at least 50% condensation product 1 or 2.

The novel compounds of general formula I can be prepared by substituting 2,2,4-trimethyl-1,2-dihydroquinoline or a further methyl group derivative of this compound under reaction conditions and proportions corresponding to the desired degree of polymerization, at temperatures between room temperature and the boiling point of the reaction mixture is reacted with an aldehyde of the general formula

R - CHO

wherein R has the meaning given above, in the presence of a catalyst, suitably an acid or one on a carrier.

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2 149332 with a large specific surface, metal oxide or metal halide is applied.

As is apparent from the general formula I, the present tri- or tetramethyl-1,2-dihydroquinoline-aldehyde condensation products contain 2-4 dihydroquinoline units which are interconnected by methylene bridges, methylene bridges may be mainly associated with the dihydroquinoline ring system in the 6 positions, but possibly also in others, especially in the 8 position.

10 In recent years, the use of antioxidant agents has become increasingly prominent - not only in industry, but also in agriculture and in human and veterinary therapy. In the industry, especially in the rubber and plastics industries, specific action and desirability of the various products are well-compatible with antioxidants, which advantageously stabilize the favorable physical properties of the various products against oxidative effects, while antioxidants used for stabilization of food and feedstuffs against oxidative damage, in addition to the good effect in many cases must also meet additional, often even counteracting or very compatible requirements. The most important requirement of this kind is harmlessness or at least low toxicity to the living organism, a broad spectrum of action and a multifaceted utility extending to numerous different substances. Thus, a particularly important area of application of such antioxidant agents is the stabilization of feed and feed mixtures, in which, in addition to the oxidation-sensitive fats and oils, and other easily decomposable organics, there is also e.g. the oxidation processes catalyzing metal salts or trace elements, as well as the stabilization of meat meal and fish meal and of various products from the food industry. The antioxidant agents suitable for such purposes must largely retain their protective effect

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3 1Λ9332 the most diverse substances under difficult conditions affecting their effect in many ways.

As a result of worldwide research carried out after use in biological systems, ie 5 e.g. for stabilizing feed mixtures suitable antioxidant agents, in the fifties, N, N '- diphenyl-p-phenylenediamine (DPPD) was proposed for such purposes; however, this compound has proved unsuitable for these purposes due to its toxicity, its carcinogenic effect and relatively low activity. In addition, 2,6-di-tert-butyl-4-hydroxy-toluene (BHT), a mixture of the isomeric 2-tert-butyl-4-hydroxy-anisole and 3-tert-butyl-4-isole. hydroxyanisol (BHA), mercaptoethylamine, polyhydroxy-diphenyl, the alkyl esters of gallic acid and 6-ethoxy-2,2,4-trimethyl-1,2-dihydroquinoline (EMQ) have been proposed as agents for such purposes. Furthermore, among these compounds, mainly BHT and EMQ are used to stabilize compound feedingstuffs, meat meal and fish meal as well as for human and veterinary therapeutic purposes, but the strict requirements regarding toxicity could also not be met with these compounds. As recommended by WHO / FAO Nutrition Meetings Report Series No. 40 A, B, C, WHO / -FAODAU 67.29 are suitable for such purposes only such antioxidant agents having LD LD values greater than 5 g / kg body weight. In contrast, by the Cornfield modified Korber method, the compounds BHT and EMQ exhibit the LD ^ Q values below.

BHT 0.892 - 0.12 g / kg EMQ 2.23 - 0.30 g / kg

In addition to the acute toxicity limit, the chronic toxicity studies also showed an unfavorable picture: doses of 0.56 g / kg EMQ may, by sustained administration to animals, cause loss of appetite and decrease weight gain ( according to study results from the Hungarian National Institute of Pharmacy). Similar adverse experiences are also made by administering doses of 0.50 g / kg for 14 days to rats: the appetite of the animals is reduced and 5 liver augmentation is observed (cf. I.F. Gaunt et al:

Food and Cosmetic Tox 3, 445-446 (1963)). Hereby, it has been found that upon administration of BHT, cholesterol synthesis is increased in the liver as well as endogenous epoxidation, and endogenous fatty acid production and β-oxidation are stimulated, and gestation time is prolonged, and among the offspring, anophthalmia is observed, suggesting a teratogenic effect, cf. G. Pascal et al .: Ann. Nutr. Alum., 23, 15--62 (1969).

A further disadvantage of EMQ is that this compound is a volatile substance, making its use in heterogeneous phase more difficult and costly.

All these facts unequivocally show that, in the field of nutrition and feeding with right requirements, far from being satisfactorily fulfilled, not even by the for the time considered the best and most frequently used anti-oxidative agents BHT and EMQ. It is therefore clear that the need for effective, said requirements fulfilling antioxidant agents still exists.

It has now been found that the antioxidant compounds of the invention are free of said disadvantages in that they are non-volatile, non-toxic and highly active.

These compounds can be prepared when 2,2,4-trimethyl-1,2-dihydroquinoline or with an additional methyl group is substituted, but at the 6-position, unsubstituted derivatives 30 of this compound (e.g., 2,2,4,7 -tetramethyl-1,2-dihydroquinoline) or salts of these compounds are transferred into the high molecular weight derivatives of general formula I by condensation with aliphatic aldehydes. This condensation reaction is conveniently carried out in solvents of 0.5-1.0 mol, advantageously 0.5-0.6 mol, al.

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5 dehydes, calculated on 1 mole dihydroquinoline derivative, at a temperature between room temperature and the boiling point of the reaction mixture in the presence of acidic catalysts. In this way, condensation products consisting of 2-4 are obtained with each other connected by methylene bridges and in any position in the aromatic rings, especially in the 6-position, to these methylene bridges, bonded dihydroquinoline units; in contrast to the monomeric basic compound, 2,2,4-trimethyl-1,2-dihydroquinoline, and to its 6-ethoxy derivative 10 (EMQ), these condensation products exhibit no detectable - neither acute nor chronic - toxicity, at the same time as , that the good antioxidant effect of the analogous monomeric dihydroquinoline derivatives, such as that of EMQ, is fully maintained or even surpassed by these condensation products. A further advantage of such condensation products is that they also exhibit chelating, i.e., heavy metal ion binding properties, and thereby can bind the oxidative processes catalyzing heavy metal ions, especially copper ions in the systems to be protected against oxidation; moreover, like the amine-type monomeric antioxidants, they are also capable of decomposing the hydrogen peroxides forming during oxidation and to bind the resulting free radicals. The degree of polycondensation of the dihydroquinoline aldehyde condensation products thus produced, i.e. the number of dihydroquinoline units present in the product is dependent on the reaction conditions used in conducting the condensation and on the proportions of the starting materials; If the above reaction conditions are met by the condensation, a mixture of condensed molecules containing mainly 2-4 dihydroquinoline units is obtained.

The antioxidant condensation products of the general formula I are novel. The one in the preparation of the condensation products of the invention

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The monomer used 2,2,4-trimethyl-1,2-dihydroquinoline is a known compound (its preparation and properties are described, for example, by Bayer: J. Prakt.

Chem., 2 ^ 33, 401 (1886) and by Combes: Bull. Soc. Chim.

-5 Pr., 49, 89 (1888). W.H. Cliffe (J. Chem. Soc. London, 1933. 1329) has also described condensation reactions for this compound with formaldehyde or with some aromatic amines; however, in the case of formaldehyde, these reactions are carried out with ca. 4 moles of aldehyde to 1 mole of dihydroquinoline derivative at 20 ° C with a reaction time of at least 2 hours, so that, as reaction products, condensation products exhibiting the secondary formula amine structure corresponding to dihydroquinoline are not obtained. the units via the heterocyclic nitrogen atom of the dihydroquinoline ring connect to tertiary amine type products which accordingly have quite different chemical and physical properties, e.g. are insoluble in hydrochloric acid, exhibit a single order of magnitude lower basicity and completely divergent chromatographic conditions, and which also lack the antioxidant effect of the condensation products of the invention. The same product, in addition to Cliffe, is also described by D. Craig (J. Am. Chem.

Soc., 60, 1458-1465 (1938)).

The condensation products of 2,2,4-trimethyl-1,2-dihydroquinoline and its substituted derivatives with formaldehyde and other aliphatic aldehydes having a structure of general formula I and accordingly a secondary amine character are thus novel. products.

Since the 2,2,4-trimethyl-1,2-dihydroquinoline molecules, under the reaction conditions of the initial preparation method of the active compounds of the invention, are essentially linked to each other with the methylene bridges formed via carbon

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7 atoms in the 6-position are obtained e.g. in the case where 1 2 R = R = H, as the reaction product bis- [2,2,4-trimethyl - 1,2-dihydroquinoline- (6)] - methane (hereinafter referred to as XAX) and its higher condensed derivatives containing 3 or 4 dihydroquinoline units, or a mixture of these compounds. In the case of these higher condensed derivatives, the additional bonding takes place in experience mainly at the carbon atom 8 of the dihydroquinoline ring.

Upon completion of the condensation reaction, the unreacted monomeric dihydroquinoline starting substance is removed from the reaction mixture; this can be done by water vapor distillation (conveniently with superheated water vapor) or by azeotropic distillation (for example, with the addition of toluene or a mixture of acetone and ethanol) or by extraction with an aqueous medium having a pH of 3-4.5 (at which pH only the unreacted starting substance is dissolved).

After this purification, whereby the unreacted starting material is removed, the reaction product can already be used directly as an antioxidant for most technical applications. However, when the product is to be used for such purposes where a higher degree of purity is required, it may be further purified by recrystallization of its mono- or disaltic or of the free base itself from aqueous or anhydrous organic solvents or by scraping it into organic solvents. dissolved base in the form of a e.g. with concentrated hydrochloric acid formed salt. The antioxidant compound precipitated in the form of an acid addition salt is then washed with acidic water and the base is released with alkalis.

The antioxidant compounds of the invention are solid crystalline substances; their physical properties are advantageous for their practical use in every respect: they are well soluble in numerous organic solvents such as benzene and other hydrocarbons.

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8 149332 carbon tetrachloride, chloroform, acetone, glacial acetic acid and dioxane, and some - even depending on the degree of polymerization - can be dissolved in methanol or ethanol. In water and in dilute alkalis they are insoluble, with dilute acids forming the addition salts; they are tasteless and airless, are not corrosive, do not attack the organics and do not become discolored, are easily dispersed in rubber and similar substances, do not tend to migrate and sweat, and are completely harmless to the living organism. Because of these beneficial properties, the novel to unknown antioxidant compounds of the invention are excellent for stabilizing both the rubber and plastics industry products and feed materials and oxidation foods.

Thus, the compound bis- [2,2,4-trimethyl-1,2-dihydroquinolyl- (6)] -methane (XAX) and its substituted derivatives with an additional methyl group and the acid addition salts of these compounds can be used. with advantage and versatility as antioxidant agents in numerous fields 20 of the industry. The compound (XAX) is particularly preferred and thus it is particularly advantageous according to the invention that R = R 2 = hydrogen and N = 1.

When used in the industry, especially as antioxidants in rubber products, these compounds 25, because of their advantageous properties, provide excellent protection, e.g. of vulcanized rubber products, against all by oxidation, aging, heat and light caused damage. Even when used in amounts of 5% by weight in rubber blends, they do not exhibit any sweat in the finished product, but already provide in amounts of 0.5-1% by weight complete protection against oxidative damage. Since they do not exhibit any toxic effects, they can also be freely used in rubber products that come into contact with the living organism. Thus, these novel antioxidant agents with the same good results are useful in rubber tires for 149332

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9 means of transport, rubber blankets, conveyor belts, rubber hoses, rubber shoe soles and other technical rubber goods, as well as toys, sanitary ware and the like for protection against oxidation and aging.

However, particular advantages are provided by the toxicity of the novel antioxidant-active agents of the invention when used in animal feed and in the food industry. These novel active substances are - as evidenced by the results of studies on both the acute and the subacute and chronic toxicities - completely free from the aforementioned adverse properties of the known active antioxidant agents, in particular their harmful effects. Thus, in rats even at doses of 5 g / kg body weight, XAX does not exhibit any toxic effects at all, and after administration of daily doses of 0.25 mg / kg for 3 weeks, no tissue or cell-damaging effects can be found. Neither administration of such daily doses for 90 days has caused adverse effects in rats; no adverse effects could be observed neither in the weight gain of the animals nor in the blood picture nor in the weight of the individual organs compared with the animals fed in the same way, but without administration of XAX.

The physicochemical properties, e.g. the molecular weight and the melting point of the compounds of the invention are primarily dependent on the degree of polymerization, that is, the value of n in the general formula I, but the antioxidant effect of the products is not affected at all by this degree of polymerization. Therefore, in the preparation of products for 30 practical purposes, it is not necessary, in the condensation product, which, besides the compound of two dihydroquinoline units, usually also contains three or four such units, to separate and isolate the dimeric compound from the 35 trimers or tetramers. For analytical purposes, this separation can be by several times recrystallization or by chromatography.

In the following, the invention is further illustrated by examples.

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Example 1 346 parts by weight of 2,2,4-trimethyl-1,2-dihydroquinoline, 500 parts by weight of methanol and 95 parts by weight of 35% formaldehyde are introduced into a reactor equipped with a heating and cooling jacket.

Then, with still stirring, this mixture is slowly added with 250 parts by weight of concentrated hydrochloric acid, taking care that the temperature of the reaction mixture does not exceed 40 ° C. Stirring is continued at this temperature (30-40 ° C) for a further 4 hours. The obtained crude reaction mixture, still containing approx. 8-15% unreacted 2,2,4-trimethyl-1,2-dihydroquinoline, then diluted with a double amount of water, filtered and the reaction product precipitated by the addition of sodium hydroxide. The solid product obtained is isolated and dissolved in toluene, then the solvent and the unreacted starting substance are removed by distillation with superheated water vapor and the residual product is recrystallized from heptane. There are thus obtained 290 parts by weight of a predominantly bis - [2,2,4-trimethyl-1,2-dihydroquinolyl- (6)] methane and 25 minor amounts of higher polymerized derivatives comprising reaction product, which melts at 83 -86 ° C.

Analysis, based on the sum formula C25H30N2:

Calculated: C = 83.80%, H = 8.38%, N = 7.82%

Found: C = 81.65%, H = 8.34%, N = 10.27%.

30 The mole cooling weight of the product measured on the basis of the increase in boiling point is 385 (calculated value based on the above sum formula: 358); the deviation from the calculated value can be attributed to the presence of higher polymerized compounds.

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Example 2

Proceed as in Example 1, but with the difference that the crude product precipitated with sodium hydroxide is dissolved in benzene and the benzene solution is repeatedly washed with a 5 aqueous hydrochloric acid solution having a pH of 4 for the purpose of removing the unreacted starting material present; after distillation of the benzene as the residue obtained, the product is then recrystallized from a mixture of acetone and water. The quantity and quality of the product obtained are similar to Example 1.

Example 3

Proceed as in Example 1, but with the difference that the pH of the reaction mixture diluted with a double amount of water is adjusted to 3-5 by the addition of sodium hydroxide solution. This precipitates the desired reaction product, leaving the unreacted starting substance in solution. The precipitated product is washed with water and dried.

The crude bis- [2,2,4-trimethyl-1,2-dihydroquinolyl- (6)] methane thus obtained is already sufficiently pure in this state for use as a technical antioxidant; for use in foodstuffs and for therapeutic use or for analytical purposes, this product may be recrystallized in the manner described above.

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Example 4 In the apparatus described in Example 1, a mixture of 346 parts by weight of 2,2,4-trimethyl-1,2-dihydroquinoline, 346 parts by weight of methanol and 346 parts by weight of water is added to 95 parts by weight of a 35¾1 formaldehyde solution or an equivalent amount. paraformaldehyde, and with vigorous stirring slowly 180 parts by weight of concentrated hydrochloric acid is slowly added, taking care, when cooling, to ensure that the temperature of the reaction mixture during the addition does not exceed 50 ° C. After 16 hours of reaction, the reaction mixture is added

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1000 parts by weight of acetone, then the pH of the mixture is adjusted by adding 50% aqueous sodium hydroxide solution of approx. 10. The aqueous / alkaline phase and the dissolved sodium chloride are separated and the solvent is evaporated from the solvent phase. The antioxidant obtained as a residue is heated in water in a closed pressure vessel to 150 ° C and, after cooling, the solidified product is pulverized. 340 parts by weight of a product are obtained, the quality of which corresponds to the quality of the product produced in Example 1 10.

Example 5 In the apparatus described in Example 1, an emulsified mixture of 346 parts by weight of 2,2,4-trimethyl-1,2-dihydroquinoline, 115 parts by weight of lacquer gasoline and 95 parts by weight of a 35% formaldehyde solution is slowly stirred with vigorous stirring. added 25 parts by weight of 50% sulfuric acid. After the completion of the approx. For 1-2 hours of exothermic reaction, the reaction mixture is kept under further stirring for 8 hours at 85-95 ° C, then the pH is adjusted by adding sodium hydroxide solution of 9-10. The free base precipitated condensation product and the dissolved sodium chloride are separated by filtration or centrifugation, the sodium chloride is washed out with water and the remaining base 25 is melted in water and allowed to cool. 341 parts by weight of the antioxidant of the invention are obtained; after recrystallization from lacquer gasoline, the product has a molecular weight of 358. 1 2 3 4 5 6

Example 6 2

The procedure described in the above Examples 3 is followed, but with the difference that the unreacted reaction 4 product is not removed by water vapor distillation or extraction from the immediately obtained reaction product, but a sample of the crude product is subjected to 149332

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13 a thin layer chromatographic study in 5% benzene solution and in this way the amount of the unreacted 2,2,4-trimethyl-1,2-dihydroquinoline present in the crude reaction product is measured. This chromatographic analysis 5 is carried out on activated silica gel plates with a system of 95% benzene, 4.97% butanol and 0.03% water which is developed with dilute potassium permanganate solution and for comparison purposes 2,2,4-trimethyl-1,2,3 dihydroquinoline solutions of known concentration. Then the crude reaction mixture obtained in the above manner is added 0.5 mol of formaldehyde for each mol of the measured content of 2,2,4-trimethyl-1,2-dihydroquinoline, and the mixture is refluxed for 1-2 hours. The reaction mixture is worked up in the manner described in the previous examples.

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Example 7 In the apparatus described in Example 1, this time also equipped with reflux, a mixture of 354 parts by weight of 2,2,4,7-tetramethyl-1,2-dihydroquinoline 20 and 600 parts by weight of methanol is added to 48 parts by weight of acetaldehyde. then, with constant stirring and cooling over 2 hours, 210 parts by weight of 33-34% hydrochloric acid are added slowly, taking care that the temperature of the reaction mixture during this addition does not exceed 50 ° C.

After completion of the addition, the reaction mixture is refluxed for 5 hours.

The pH of the reaction mixture is adjusted with 50% sodium hydroxide solution of 9-10, then the solvent is distilled off. The product obtained as the residue is melted in 30 water under pressure at 120-140 ° C. Thereafter, the pressure is abolished, thereby avoiding unreacted starting material with the water vapor. In this way, 320 parts by weight of a yellowish-brown product, the molar weight of which is about 450; upon heating, it begins to soften at 82-84 ° C, but exhibits no sharp melting point. The product is well soluble in hot plant oils and 14

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149332 fats: its oxidation-inhibiting effect measured in Wartburg apparatus reaches approx. 80% of the effect of XAX.

The above process can also be carried out so that instead of the above 600 parts by weight of methanol 5, 900 parts by weight of 80% acetic acid is used, otherwise proceed in the manner described. The same product is available in the same quantity.

Example 8 10 358 parts by weight of bis- [2,2,4-trimethyl-1,2-dihydroquinolyl- (6)] methane are dissolved in 700 parts by weight of benzene and 36.5 parts by weight of dry hydrogen chloride gas are passed into the solution.

The monohydrochloride precipitated in quantitative yield is filtered off and dried. The water-soluble monohydrochloride soluble in water and alcohols obtained after recrystallization from ethanol at 219 ° C.

Example 9 358 parts by weight of bis- [2,2,4-trimethyl-1,2-dihydroquinolyl- (6)] methane are dissolved in 1000 parts by weight of acetone and 73 parts by weight of dry hydrogen chloride gas are passed into this solution. The dihydrochloride precipitated in crystalline form is filtered off and recrystallized from water or ethanol.

The dihydrochloride-soluble dihydrochloride soluble in this way melts at 235 ° C.

Proceeding in the same way, but instead of dry hydrogen chloride gas, an equivalent amount of at least 30% hydrochloric acid is added to the acetone solution, the dihydrochloride is obtained in the same amount and quality.

When proceeding in the same way, but instead of hydrochloric acid, 98 parts by weight of concentrated sulfuric acid is added to the solution of the base, water-soluble sulfuric acid addition salt of XAX is obtained.

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Example 10

The antioxidant effect of the novel agents exhibited in foodstuffs and feedstuffs is investigated on fish meal samples in comparison with various well-known, but due to their toxicity for such purposes, no known, advantageous antioxidant agents, namely with 2,2,4-trimethyl-1,2-dihydroquinoline (EMQ) and 2,6-di-tert.butyl-4-hydroxy-toluene (BHT). In these experiments, the oxygen uptake of fish meal samples containing the various antioxidant agents is measured as well as to control the oxygen uptake of fish meal samples without antioxidant agents in a Wartburg apparatus at 29 ° C, and then the peroxide number of the oxygen treated samples is also determined. The experimental results thus obtained are compiled 15 in the following table; from these results, it is clear that the fish meal samples stabilized by the agent XAX according to the invention absorb a substantially smaller amount of oxygen than the samples stabilized with the known antioxidant agents or those containing no antioxidant agents at all; It is particularly striking, however, that the fishmeal stabilized with the agent of the invention after the treatment with oxygen has a significantly lower peroxide number. Thus, these experiments have shown that the compounds of the invention also in fishmeal, which has a strong tendency to oxidation and contain 30% of unsaturated oils, provide a significantly better protective effect than the known antioxidant agents.

Oxygen uptake Peroxide number (lowering of O2- (calculated on. _ Pressure in mm / kq)) 1 g fishmeal 40 g fishmeal (control) 19.5 7.83 40 g fishmeal + 0.04 g EMQ 23.5 2.87 40 g fish meal + 0.04 g BHT 16.5 3.42 40 g fish meal + 0.04 g XAX 11.5 1.54 35 -;