DE1618727A1 - Process for the preparation of 4-hydroxyenals - Google Patents

Description

Nitrite Factory GmbH & Go. in Feldkirchen b. Munich

Process for the preparation of 4-hydroxyenals.

The invention relates to the production of k- hydroxyenals, for example 4-hydrosyoctenal. So far, compounds of this type could only be obtained as partial products by the process of patent 1,134,180. Due to the present charge, the production is also made possible by synthetic means,

4- Hydroxyeaals represent pharmaceutical-int "r" is "si ^ 9 substance, inato peculiarities inhibit the Ätmusg ui ^ L GÄFisisg of Karzinoraz @ ll®a. This heamraig is due to the inactivation of the fermentation enzymes ßlje © Finald®hydphoephßtd @ hydi * ögenaaa and

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Explain lactic acid dihydrogenase by the substances mentioned.

In this way they cause an inhibition of the tumor growth

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turns. It was found that in metabolic measurements on EHELICH ascites carcinone in mice with the previously unknown hydroxyoctenal, anaerobic fermentation of 15 million tumor cells at a concentration of 3 χ 10 m / 1 is 100 % blocked. With the same pretreatment, the respiration of the cells is inhibited by 95% at a concentration of 4 × 10 "m / 1.

Nevertheless 4-hydroxyenals are very effective cell toxins, They also damage in comparison to the experiments with the cancer cells in 12 - 15-fold higher concentration and at 50 - 60 times lower cell density the breathing of healthy ones Cells don't.

The EHHLICH ascites carcinoma cells are thus killed by 4-hydroxy-2,3enals under conditions under which Cells of healthy organs are not yet noticeably damaged.

-. * .. The preparation of the 4-hydroxyenals according to the invention

This is done in such a way that, starting from acrolein, the propargyl diethyl acetal is first prepared by bromination and elimination of hydrogen bromide with simultaneous conversion of the aldehyde group into the acetal form, and this by means of a Grignard see reaction in the corresponding magnesium

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bromidprouargyldiäthylacefcal transferred. Starting from this Intermediate stage, a carbon chain can be made more desirable by reacting with various aromatic and aliphatic aldehydes Length to be built up »Subsequently, the magnesium-containing residue is split off and the i ^ droxyl group is introduced treated with water, then the triple bond with lithium aluminum hydride hydrogenated to the double bond in iransposition and finally the aeetal group in a weakly acidic solution to the free * Mlydroxyenal saponified.

The chain length of the 4-hydroxyenal produced by the process according to the invention results from the number of carbon atoms of the aliphatic aldehyde reacted with the magnesium bromide propargyl diethylacetal. In this way, a group of 4-hydroxyenals was obtained which have boiling points which increase with increasing chain length. Dis to '• a chain length of 10 C atoms, the hydroxyeaals obtained can be vacuum distilled. Higher hydroxyenals such as 4-hydroxyundecenal, 4-hydroxy-, duodecenal and k- hydroxytridecenal can no longer be distilled without decomposition.

Example;

a) Production of dibromoacrolein

168 ir (J Hol) acrolein are in 400 ml of chloroform itself.

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A solution of 450 g of bromine in 150 ml of chloro form is added dropwise in the course of 8 hours at -5 °, After the chloroform was evaporated in a water jet vacuum, the Dibromacrolein is at a pressure of 10-12 mm Hg ^- distilled. Bp. 70-85 ⁰ C. Yield 70-75%.

b) Production of the dibromacroleindiäthylacetals

g of dibromacrolein are added dropwise to a mixture of 3 ^ 0 ml of ethyl orthoformate and ^ 70 ml of absolute ethyl alcohol at -5 ° C. The mixture is left to stand for about 6 hours and then excess ethyl alcohol and ethyl orthoformate and the ethyl formate formed are distilled off at normal pressure. The mixture is then distilled in a vacuum at 10 mm Hg up to a boiling point of 10 ^{° C.} The residue obtained is oily and spelled yellow in color.

c) Manufacture of Propargy! acetals

the dibromoacroleindiethylacetal obtained according to b) is slowly added with vigorous stirring to a solution of 6 mol of KOH in 1.5 l of alcohol. Here, the temperature rises to 70 to 75 ⁰ G. was filtered out from the precipitated potassium bromide and heated the Löeung 3 hours reflux. The »potassium bromide which is separated out is then filtered off, whereupon the largest,

Part of the ethyl alcohols distilled off on a column. The distillation is stopped when the L ^r transition temperature is 9O-95 ° C and the remaining residue in ethyl alcohol

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5 liters of water are added to the propargyl acetal dissolved therein. The aqueous solution is extracted 3 times with 500 ml of chloroform each time. The combined chloroform extracts are dried with sodium carbonate. After the chloroform has been distilled off, the residue is distilled. Here Propargylacetal is with a Kp from 138 - 144 ⁰ C obtained with an acetal based on the charged Dibromacroleindiäthy yield of 60-75 7>.!.

d) Establishing the Grignard connection

0.05 mol of ethyl bromide, which is dissolved in a few ml of absolute tetrahydrofuran, is added to 0.3 mol of magnesium in j ^ orm of chips in 50 ml of absolute tetrahydrofuran. As soon as the reaction has started, the rest of the ethyl bromide (0, 25 mol) dissolved in 50 ml of tetrahydrofuran are slowly added with stirring, the reaction being controlled so that the mixture refluxes. After completion of the addition stirring is continued for another 45 minutes uter reflux, allowed to cool to room temperature and then cooled further with stirring to T-IO ⁰ C from. The ethylmagnesium compound precipitates out as a crystalline paste. To this suspension is added dropwise with stirring 0.15 mol Propargylacetal dissolved in 25 ml of tetrahydrofuran, In the reaction, the temperature should not exceed - 5 ° C rise ₀ After completion of the addition "stirred at 0 for 2 hours at -10 °,

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β and f) Preparation of the 4-Hydrox.y ^ naldiethy! acetal to the mixture obtained in stage d is slowly added dropwise with stirring at .10 to -5 ° C 0.3 mol of aldehyde in 5c ml of absolute tetrahydrofuran. After the addition has ended, the mixture is stirred at -5 ° C. for 3 hours. 20 ml of semi-saturated ammonium chloride solution are then very carefully added dropwise with vigorous stirring. The temperature should not ^{rise above +10 0} C here. The mixture is stirred for 30 minutes, about 100 ml of water are added and the mixture is stirred until two clear phases have formed. After separation, the lower phase is extracted three times with 100 ml of diethyl ether each time and combined with the upper phase. Without drying it beforehand, the ether is evaporated in vacuo. The residue is taken up with chloroform and dried with sodium carbonate. After evaporation of the solvent, one fractionates la vacuum with the addition of a little sodium carbonate over a small, effective column. Table 1 shows the yield based on the propargyl diethyl acetal used and the boiling points of the hydroxinal diethyl acetals thus obtained.

η Table 1 Boiling point Ed 'Inserted 0 yield Ed aldehyde 1 84 ° / 0.8 mm Hg ■ Acetaldehyde; 2 7 »* - 84 * 88 / fO ° / O, 7ω 'Ed Propionaldehyde 3 75Ji - 80 * 102 ° / 1 .mm Ed Butyraldehyde if 75J < 110 ° / 0.7 »m Ed Pentanal 5 78 * 118 ° / O, 7 mm Ed Hexanal 6th 80 * 129 ° / 0.8 am Ed Heptanal 7th 72 * 143 ° / O, 7 mm Ed. Ootanal 8th 46 * 127 ° / 0.3 mm •? h '<: Nonanal , - 55% 137 ° / 0.3 mm Decanal 62 * OBJQJNAl

g) Hydrogenation to Hydroxyalkendläthy! acetal to 0.1 mol of lithium aluminum hydride in 100 ml of absolute tetrahydrofuran is added dropwise with good stirring at -25 to -20 ⁰ CO ₁ I mol of hydroxyalkinal diethyl acetal. After completion of the addition 5-7 hours is stirred at -25 to -20 ⁰ C. For hydrolysis, 20 tablespoons of semi-saturated ammonium chloride solution are carefully added dropwise and the mixture is stirred for 30 minutes. The solvent is filtered off with suction and the solvent is evaporated off in vacuo. The residue is taken up in chloroform and dried with sodium carbonate. The chloroform is evaporated off and fractionated in vacuo using a small, effective column. The yield is in all cases 1 * 0-500 of hydroxyalkenaldiethylacetal in relation to the hydroxyalkinaldiethylacetal used. Table 2 shows the boiling points of the 4-hydroxyalkenal diethyl acetals of various chain lengths obtained on this catfish.

Table 2

k- Hydroxyalkenaldiethy! acetale η Kp

4-hydroxypentenal diethylacetal 0 80 ° / 82 ° / l _t l mn Hg

"■ hexenal ■ · 1 85- 86 ° / 0.7 mm Hg

"" heptenal ■ · · 2 9! fr ^o / l, Q mm Hg

"■ octenal ■. ■ 3 108 ° / 0.7 mm Hg

■ "nonenal ■ · k I15 ° / O _f 7 mm Hg "· decenal ■ ■ 5 128 ° / 0.8 mm Hg

■ "undecenal ■ ■ ■ 6 120 ° / 0.3 mm Hg "" dodecenal ■ · ■ 7 127 ° / 0.4 mm Hg "" tredecenal. ■ ■ β * .-—.

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h) Saponification to give the corresponding hydroxyenals 10 ml of hydroxyalkenaldiathylacetal are mixed with the same volume of ΙΟ / fig citric acid and left to stand for 60 minutes. In the case of higher chain lengths (from hydroxyoctenal), 10 ml of alcohol are also added and the mixture is stirred vigorously for 1 hour. The aldehyde is extracted with chloroform, the water is frozen out at -25 ° and the chloroform is evaporated off in vacuo. The residue is fractionated in vacuo. The yield of 4-hydroxyalkenal is in all cases 90-100% based on the hydroxyalkenal diethyl acetal used. Table 3 gives the boiling points of the distillable hydroxyalkenals.

Table 3
^ -Hydroxyalkenals η Kp

H- hydroxypent enal ¹¹ hexenal 0 58 ° / 0.3 mm Hg It ^M heptenal 1 70 ° / E, 7 mm Hg η "octenal 2 76 ° / 0.5 mm Hg η ^M nonenal 3 85 ° / 0.3 mm Hg H ^M decenal k "91 ° / O, 3 mm Hg ti "unäecenal 5 127 ° / Ο, ό ram ed ti ¹¹ dodeoenal 6th not undecomposed distillery: M. "tredecenal 7th Il Π fl Il 8th I! Il H

BATH

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Claims (1)

Claims Process for the production of 4-hydroxyanals of the general jargon R-GH-CH = CH-C = O OH H. in the R means: - where η is an integer from 0 to 8, characterized in that in each case known per se Acrolein a) by adding bromine to the double bond in dibromacrolein (Dibromopropanal) transferred b) this with orthoformate in the presence of ethyl alcohol converts corresponding dlbromacroleindiethylacetal, c) which by treatment with alkali, preferably alcoholic Potassium hydroxide solution with double elimination of hydrogen bromide propargyl diethyl acetal results in the d) converted into the corresponding magnesium bromide propargyl diethyl acetal according to Grignard by adding ethyl magnesium bromide will, θ) to which carbonyl compounds in the form of aliphatic © the aromatic aldehydes are added, whereupon the resulting compounds 609883/2156 BAD ORIGINAL ·· - ίο - f) for the purpose of forming an OH group and for splitting off the metallic best to be treated with water g) and the product is hydrogenated by means of Llthiumalueiniumhydrid to form a double bond in transposition, whereupon h) the acetal group to the free in weakly acidic solution 4-Hydroxyenal is saponified. BATH ORIGINAL 009883/2156