DE1059900B - Process for the preparation of compounds of the vitamin A series - Google Patents

Description

Process for the preparation of compounds of the vitamin. A-row In The last twenty years there have been numerous processes for the synthesis of the vitamin A and its biologically active derivatives, e.g. B. the vitamin A alcohol ester, the Vitamin A acid and its esters, vitamin A aldehyde, vitamin A ether, des Dimethylaminovitamins A and the axerophthalene (deoxyvitamin A) became known.

About the older work give z. B. Information: The summarizing Reports by 0. Isler, Chimia, Vol. 4, 1950, pp. 103ff .; by J. G. Baxter, Advances of chemistry org. Natural substances, Springer-Verlag, Vienna, Vol. 9, 1952, p.41ff .; from H.0. Huiman and coworkers, Recueil des Travaux Chim. des Pays-Bas, Vol. 71, 1952, p.911; by N. A. Milas, #> The Vitaminesa, Vol. 1, Acad. Press. Inc. Publishers, New York, 1954, pp. 4 to 58.

More recently, other methods have been used, for. B. by the German patents 873 240, 894 691, 918 987, 950 551,950 552, 951212, 957 942, 1001256 and 1001258, the French patents 1098 615 and 1108 113 as well as the USA patents 2 789 131, 2 680 755, 2,674,621, 2,676,988, 2,676,989, 2,676,990, 2,676,991, 2,676,992, 2,676,993, 2,676,994 and 2,766,290 are known.

Only very few of the known processes lead to crystalline, pure end products. Therefore, only a few of these processes are of technical importance attained. One of the main reasons for this is the easy transition of the vitamin A double bond system into the so-called retro system.

In the above-mentioned processes, the predominant starting material used is the f-ionone. In a very careful and critical investigation, H. 0. Huisman et al., Recueil des Travaux Chim. des Pays-Bas, Vol. 71, 1952, p. 899, and Vol. 75, 1956, p. 977, found that, apart from a few exceptions - to which the process later made known by the German patent specification 950 551 is to be counted -, all vitamin A syntheses with ß-ionone as the immediate starting material initially lead predominantly to compounds of the retro-vitamin A series. This means that an allyl shift in the direction of the ring has occurred, whereupon compounds of the general formula after elimination of water develop. R stands for - CH = CH - R 'or for - C Hz - CH = CH - R' and R 'for a saturated or unsaturated aliphatic radical which can contain terminal functional groups.

Therefore it has not been possible up to now to easily remove the ß-ionylidene ethanol (IV), which is important for the synthesis of vitamin A, by allyl shifting from the ethynylation of ß-ionone (I) and partial hydrogenation of the ethynyl-ß-ionol (II) accessible 5 - [2 ', 6', 6 '-trimethylcyclohexene- (1') -y1- (1 ')] -3-methylpentadiene- (1,4) -ol- (3) (W. Oroshnik, G. Karmas and A. Melbane, J. Am. Chem. Soc., Vol. 74, 1952, p. 300) (11I) (vinyl-β-ionol); The main product was always the corresponding retro-compound of the formula V with dehydration. It has now been found that, starting from vinyl-β-ionol (III), compounds of the vitamin A series are obtained in a single process step with good yields and without the formation of compounds of the retro-vitamin A series if the vinyl is used -ß-ionol (III) with a hydrohalide of a triarylphosphine and with an unsaturated aldehyde of the general formula in which R denotes a CH 2 O H group, an esterified or etherified C HZ O H group, a COO H group, an esterified COO H group, a - C HZ N (C H3) 2 group or a CH, 7 group , in the presence of acid-binding agents, preferably of alkali or alkaline earth alcoholates, or in an aqueous or alcoholic medium in the presence of alkalis or alkaline earths, and advantageously in the presence of an organic solvent which is inert under the reaction conditions.

As an organic solvent under the reaction conditions are indifferent, d. H. dealing with the acid-binding agents used as well not with the ylides of phosphorus, which are likely to occur as intermediate products implement, be z. B. ethers such as diethyl ether, tetrahydrofuran, dimethyltetrahydrofuran and dioxane, hydrocarbons such as benzene, toluene, xylene, cyclohexane, cyclooctane and isooctane, alcohols such as methanol, ethanol, isopropanol, propanol, the butanols and benzyl alcohol, or dimethylformamide and N-methylpyrrolidone.

The reaction temperature can be within wide limits, namely between about -50 and -i-- 100 ° C are selected; however, temperatures below are advantageous 0 ° C. The starting materials are advantageously used in equimolar amounts. The amount of acid-binding agent, depending on the choice of the aldehyde component, z. B. if R = C O O H is to be a multiple of what is theoretically required. An over shot of the In fact, alcoholate is often beneficial.

For the synthesis of vitamin A acetate (VII) from vinyl β-ionol (III), triphenylphosphine hydrochloride, γ-acetoxy-methylcrotonaldehyde (VI) and sodium methylate, the new process can be formulated as follows: The compounds of the all-trans series are formed under the conditions specified in the following working examples. However, if all isomerizing influences, such as light and acid, are avoided when working up the products of the process, then in addition to the compounds of the all-trans series, the extremely easily isomerizable compounds of the 11,12-cis-vitamin A series can be obtained. Retro-vitamin A compounds were not observed in any case.

The new process for the synthesis of compounds of the vitamin A range is much simpler and requires fewer process steps than the known ones Procedure. Another advantage is the high degree of purity of the end products, which are easy to use can be obtained in crystalline form. The novelty of the principle of condensation and its Superiority through fewer stages, better yields and, in particular, through the pure and crystalline form of the final products will be in all-trans configuration z. B. very clearly, if you consider the new process with the US. Patent specification 2 674 621 and 2 789 131 are compared, which also contain ethynyl-ß-ionol is used as a starting material.

The vitamin A and other biologically active compounds of the vitamin A series are valuable pharmaceuticals and because of their physiological effectiveness Additives for animal feed. The parts mentioned in the examples are parts by weight.

Example 1 70 parts of triphenylphosphine hydrochloride are mixed with 44 parts of 5- [2 ', 6', 6'-trimethylcyclohexen- (1 ') -yl- (1')] -3-methapentadiene- (1,4) -o1- (3 ) stirred in 200 parts of absolute alcohol for 6 hours at room temperature. The resulting solution is simultaneously added dropwise with 100 parts of a 31 ° / jgen methanolic sodium methylate solution at -15 ° C in a nitrogen atmosphere to a solution of 30 parts of β-formylcrotonic acid in 50 parts of absolute alcohol. The mixture is stirred for a further 1/2 hour at -15 ° C. and then acidified at + 5 ° C. with 250 parts of 1,5-n-phosphoric acid. The crystals which precipitate are filtered off, washed with water and methanol and dried in vacuo. 42 parts of crude vitamin A acid with a melting point of 170 ° C. are obtained which, after recrystallizing once from methanol, has a melting point of 178 ° C., Am " = 350 to 351 p" E = 42,000. Example 2 70 parts Triphenylphosphine hydrochloride is mixed with 44 parts of 5- [2 ', 6', 6'-trimethylcyclohexen- (1 ') -yl- (1')] -3-methylpentadien- (1,4) -o1- (3) in 150 parts The solution is added simultaneously with 70 parts of a 31% methanolic sodium methylate solution at -15 ° C in a nitrogen atmosphere to a solution of 25 parts of tiglic aldehyde in 25 parts of absolute alcohol and the reaction mixture is added for 1 hour at -15 C. and then for 12 hours at 20 ° C. The solution is then acidified with 75 parts of 3N hydrochloric acid and extracted with petroleum ether. The petroleum ether extracts are washed neutral with water and dried over sodium sulfate. After the petroleum ether has been distilled off, 40 parts of oily remain Residue on cooling in an ice bath crystalline solidified. The crystals are digested with a little acetonitrile and filtered off. The crude axerophtene obtained in this way has a melting point of 67 ° C., Amdx = 325 #t, E = 45,000 (in cyclohexane) and, after being recrystallized once from acetonitrile, has a pure melting point; F. 76 ° C, @ "max = 325 to 326 E = 50,000. Example 3 70 parts of triphenylphosphine hydrochloride, 44 parts of 5 - [2 ', 6', 6 '-trimethylcyclohexene - (1') -y1- (1 ' )] -3-methylpentadiene- (1,4) -ol- (3) are stirred in 200 parts of absolute alcohol for 3 hours at 20 to 25 ° C. This solution is stirred under nitrogen at -30 to -40 ° C. simultaneously with the A solution of 9 parts of sodium in 100 parts of alcohol is added dropwise to a solution of 34 parts of ß-formylcrotonic acid ethyl ester.The mixture is stirred for 1/2 hour at -10 ° C., then for 2 hours at + 20 ° C. Hydrochloric acid acidified and extracted with petroleum ether. The petroleum ether extract is washed neutral and dried over sodium sulfate. After the petroleum ether has been distilled off, 50 parts of crude vitamin A acid ethyl ester,% "" x = 352 #t (in methanol), s = 30,500, remain 4 68 parts of triphenylphosphine hydrobromide, 44 parts of 5 - [2 ', 6', 6 '-trimethylcyclohexene- (1') -y1- (1 ')] -3-methylpentadiene- (1,4) -ol- (3) and 150 parts of dimethylformamide we Stirred for 2.5 hours at -5'C and 16 hours at + 20'C. The mixture is then cooled to -40 ° C. After addition of 42 parts of ß-formylcrotonic acid ethyl ester, 36 parts of 31% methanolic sodium methylate solution are added dropwise. After 20 minutes, the cooling bath is removed and the mixture is stirred until it has reached a temperature of -f -10 ° C. After acidification with 100 parts of 10% sulfuric acid, the solution is extracted with petroleum ether. The petroleum ether extracts are washed neutral with water and sodium bicarbonate solution and dried over sodium sulfate. After the petroleum ether has been distilled off, 50 parts remain as an oily residue, which is distilled in a high vacuum, 33 parts of vitamin A ethyl ester being obtained as a yellow oil with a boiling point of 168 to 172 ° C, A.ritdx = 351 to 352 V ,, s = 38,000 (methanol). Example 5 70 parts of triphenylphosphine hydrochloride, 44 parts of 5 - [2 ', 6', 6 '-trimethylcyclohexen- (1') -y1- (1 ')] -3-methylpentadiene- (1,4) -ol- (3) and 200 parts of absolute tetrahydrofuran are stirred at 20 to 25 ° C for 6 hours. The solution is cooled to -40 ° C. under nitrogen and 35 parts of ß-formylcrotonic acid ethyl ester and 70 parts of a 31% methanolic sodium methylate solution are added dropwise at the same time. The mixture is then stirred for a further 1/2 hour at -30 ° C. and 18 hours at 20 ° C., acidified with 150 parts of 10% phosphoric acid, and the acidic solution is extracted with petroleum ether. After the petroleum ether extract has been washed neutral and the petroleum ether has been distilled off, 45 parts of residue remain. 26 parts of vitamin A ethyl ester with a boiling point of 1.165 to 170 ° C. are obtained therefrom by distillation in a high vacuum. Example 6 70 parts of triphenylphosphine hydrochloride, 44 parts of 5- [2 ', 6', 6'-trimethylcyclohexen- (1 ') -y1- (1')] -3-methylpentadiene- (1,4) -ol- (3) and 150 parts of methanol are stirred at about 20 ° C for 10 hours. The light yellow solution is cooled to -15 ° C. and 70 parts of a 31% methanolic sodium methylate solution and a solution of 34 parts of γ-acetoxy-α-methylcrotonaldehyde in 50 parts of methanol are simultaneously added dropwise from two separate dropping funnels under nitrogen. The mixture is stirred for a further 2 hours at -10.degree. C. and 12 hours at approximately 20.degree. The dark reaction solution is acidified with 75 parts of 3N hydrochloric acid and extracted with petroleum ether. The petroleum ether extracts are washed neutral with water and dried over sodium sulfate. plan now concentrates the light yellow petroleum ether solution after the addition of 0.3 part of α-tocopherol in a stream of nitrogen to about 150 parts by volume and filtered through a small aluminum oxide column (activity 2 to 3 according to Brockmann). The filtrate is freed from petroleum ether in vacuo. In a short-path distillation unit, low-boiling components are distilled off at 0.0001 Torr and around 65 to 70 ° C. The residue is 71 parts and shows am @ x = 324 to 325 #t, s = 31500 (isopropanol). For further purification, the vitamin A acetate concentrate obtained in this way is dissolved in 60 parts of hexane and chromatographed on aluminum oxide (activity 3 to 4 according to Brockmann). After a forerun, which consists essentially of the dehydration product of vinylβ-ionol, pure all-trans-vitamin A acetate is eluted, which partially crystallizes when left to stand in a little methanol at -E- 5'C, F. 57 to 58 ° C, Am " 325 E = 48,000 (isopropanol). Example 7 360 parts of triphenylphosphine hydrochloride, 220 parts of 5 - [2 ', 6', 6 '-trimethylcyclohexene - (1') -y1- (1 ')] - 3 -methylpentadien- (1,4) -ol- (3) and 800 parts of methanol are stirred for 90 hours at room temperature.This solution is simultaneously mixed with 370 parts of 6.2 N-methanolic potassium hydroxide solution under nitrogen to form a solution cooled to -40 ° C 150 parts of ethyl β-formylcrotonate in 160 parts of methanol are added dropwise, stirring is continued for 45 minutes at -30 ° C. and 4 hours at room temperature, 400 parts of petroleum ether are then added and the precipitate which separates out is filtered off. The filtrate is mixed with 500 parts of water added and extracted with petroleum ether. The combined petroleum ether extracts are washed with water, 5 ° (@ger sulfuric acid and sodium carbonate solution washed neutral and dried over sodium sulfate. After the petroleum ether has been distilled off, 220 parts of crude vitamin A ethyl ester remain as a yellow oil in the residue. Am ", = 353 p. (In methanol), a = 29,600. Example 8 68 parts of triphenylphosphine hydrobromide are introduced into 100 parts of vinyl-β-ionol with vigorous stirring and cooling in an ice bath, the temperature rising to about 35.degree. The increasingly viscous mixture is stirred for a further 15 hours, then 30 parts of β-formylcrotonic acid methyl ester are added at + 5'C and 11 parts of solid sodium methoxide are added at the same temperature 150 parts of petroleum ether are added and worked through. The petroleum ether layer is separated off, washed neutral with water and dried over sodium sulfate. After the petroleum ether has been distilled off, 75 parts of an oil are obtained, from which all volatile constituents are removed at a bath temperature of 90 ° C. in a high vacuum.

The residue left behind is 22 parts of oily vitamin A methyl ester [2m " = 354 V,; a = 10,500], which can be purified in the usual way.

Claims (4)

PATENT CLAIMS: 1. Process for the preparation of compounds of the vitamin A series, characterized in that 5- [2 ', 6', 6'-trimethylcyclohexen- (1 ') - yl- (1')] - 3-methylpentadiene - (1,4) -o1- (3) (vinyl-ß-ionol) with triarylphosphine hydrohalides and an unsaturated aldehyde of the general formula in which R is a C 112 0 H group, an esterified C HZ 0 H group, an etherified C H2 0 H group, a C 0 0 H group, an esterified COO H group, a CH, N- ( CH3) 2 group or a CH3 group is reacted in the presence of acid-binding agents and advantageously an inert organic solvent at about -50 to -f-100 ° C., advantageously below 0 ° C., and the reaction products are isolated in the customary manner. 2. Procedure according to claim 1, characterized in that the acid-binding agent used is alkali or Alkaline earth alcoholates or alkali or alkaline earth metal hydroxides in an alcoholic medium used. 3. The method according to claim 1, characterized in that there is used as triarylphosphine hydrohalide Triphenylphosphine hydrochloride is used. 4. The method according to claim 1, characterized in that that the reaction products are isolated in the presence of mineral acids.