DE1046612B - Process for the production of vitamin A and its biologically active derivatives - Google Patents

Description

Process for the production of vitamin A and its biologically active substances Derivatives In the last twenty years there have been numerous methods for synthesis of vitamin A and its biologically active derivatives, e.g. B. the vitamin A alcohol ester, vitamin A acid and its esters, vitamin A aldehyde, vitamin A ether, of Dimethylaminovitamins A and Axerophthens (deoxyvitamin A) became known.

About the older work give z. B. Information: The summarizing Reports by O. Isler, Chimia, Vol. 4, 1950, pp. 103 ff .; by J. G. Baxter, Advances of chemistry org. Naturstoffe, Springer-Verlag, Vienna, Vol. 9, 1952, p. 41 ff .; from H. O. Huisman and coworkers, Recueil des Travaux Chim. des Pays-Bas, vol. 71, 1952, P.911; by N. A. Milas, "The Vitarnines", 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, 951 212, 957 942, 1001256 and 1001258, the French patents 1098 615 and 1 108 113 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 Retrosy system.

In the processes mentioned above, the starting material used is predominantly the ß-ionone. In a very careful and critical investigation, HO 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 first practice @ iegend lead to compounds of the retro-vitamin A series, or that all vitamin A syntheses, which are based on intermediates of the general FnrmPl apparently lead predominantly to compounds of the retro-vitamin A series. This means that an unexpected shift in the allyl oil has occurred in the direction of the ring, whereupon, after elimination of water, compounds of the general formula develop. R stands for - CH =CH - R 'or for - C H2 - CH =CH - R', and R 'stands 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'-trimethylcyclohexen- (1 ') -y1- (1') -] -3-methylpentadien- (1,4) -ol (3) (W. Oroshnik, G. Karmas and A. Melbane, J. Am. Chem. Soc., Vol. 74, 1952, p. 300) (III) (vinyl β-ionol); The main product was always the corresponding retro-compound of the formula V with dehydration. Surprisingly, it has now been found that by reacting the previously unsuitable retro-compound of the formula V, 5- [2 ', 6', 6'-trimethylcyclohexene (2 ') -ylidene- (1')] -3-methylpentadiene - (1,3), with a hydrohalide of a triarylphosphine or with triarylphosphine in the presence of hydrogen halide and an unsaturated aldehyde of the general formula in which R is a CH20H group, an esterified or etherified C H2 O H group, a COO H group, an esterified COOH group, a CH, N (CH3) 2 group or a saturated or unsaturated aliphatic radical, preferably one CHg group means, in the presence of acid-binding agents and in the presence of solvents, vitamin A and its biologically active derivatives are obtained directly.

Suitable acid-binding agents are, for. B. Alkali and alkaline earth alcoholates as well as alkali and alkaline earth hydroxides.

Suitable solvents are when using alkali or alkaline earth metal alcoholates those with these and n-it the intermediate probably occurring V tides the phosphorus do not undergo any self-reactions, e.g. B. ether, tetrahydrofuran, dimethyltetrahydrofuran, Dioxane, hydrocarbons such as benzene, toluene, xylene, cyclohexane, cyclooctane, isooctane, Dimethylformamide, dimethylpyrrolidone, alcohols such as methanol, ethanol, isopropanol, Propanol, butanol and benzyl alcohol, or mixtures of such solvents .. When using alkali or alkaline earth hydroxides, the solvents can, if they are miscible with water, e.g. B. methanol, ethanol and dimethylformamide, too this included.

The reaction temperature can be within wide limits from -50 to + 100 ° C be varied; Temperatures below 0 ° C. are particularly advantageous. The initial good is advantageously used in a molar ratio, but the proportion of acid binding agent several times the equimolar amount, e.g. B. if in the aldehyde the radical R = - C O O H is. Even in the presence of excess triarylphosphine hydrohalide larger amounts of the acid-binding agent are appropriate.

Since triphenylphosphine is particularly easily accessible, its Hydrohalides, e.g. B. the hydrochloride or hydrobromide, preferably used.

The triarylphosphine hydrohalides do not necessarily have to be prepared in pure form beforehand; the corresponding triarylphosphines in the presence of hydrohalic acids can also be used in their place. For the synthesis of vitamin A acetate (VII) from 5- [2 ', 6', 6'-trimethylcyclohexen- (2 ') - ylidene- (1')] - 3-methylpentadiene-1,3 (V), Triphenylphosphine hydrochloride, γ-acetoxy-a-methylcrotonaldehyde (VI) and sodium methylate, the new process can be formulated as follows: \ / CH-CH = C-CH = CH, OHC-C = CH- CH, -OOCCH3 CH3 + CH3 V VI z. B. Dimethylformamide + [(C6 H5) 3 PH] + C1- as solvent + Na OC H3 \ j CH = CH-C = CH-CH = CH-C = CH-CH2-OOCCH3 CH, C H3 j. \ VII + (C.H5) 3P0 - + NaCl + CH30H 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 vitamin A and its biological effective derivatives is much simpler and requires fewer process steps than the known.

The special value of the new teaching lies in the fact that one is now a retro connection Can process as a starting material and compounds with the vitamin A constitution receives.

Vitamin A and its biologically effective ones described in more detail at the beginning Derivatives are valuable physiologically active substances that are used as pharmaceuticals and gain increasing importance as additives for animal feed.

The parts mentioned in the examples are parts by weight.

Example 1 220 parts of vinyl-β-ionol (cf. W. Oroshnik, G. Karmas and A. Melbane, J. Amer. chem. Soc., Vol. 74, 1952, p. 300) are benzene in 500 parts solved. After adding 0.3 part of p-toluenesulfonic acid and 0.5 part of a-tocopherol the mixture is heated to boiling and the benzene is distilled off. The emerging Water is withdrawn from the distillate and the distilled benzene continuously returned to the reaction vessel. If no more water formation occurs, will the mixture cooled and the red-yellow benzene solution first with aqueous bicarbonate solution and then shaken out with water. After drying over sodium sulfate, the Benzene evaporated and the residue distilled. 165 parts of 5- [2 ', 6', 6'-trimethylcyclohexen- (2 ') - ylidene- (1')] -3-methylpentadiene-1,3 are obtained (V) of bp a, l = 72 ° C, A. "" (hexane) 313 mu.

100 parts of 5- [2 ', 6', 6'-trimethylcyclohexen- (2 ') - ylidene- (1')] -3-methylpentadiene -1.3 (V) are mixed with 150 parts of triphenylphosphine hydrochloride in 200 parts of dimethylformamide 12 Stirred at + 10 ° C for hours. Then the yellow solution is cooled to -10 ° C. 40 parts of tiglic aldehyde and 87 parts of a 30% strength methanolic sodium methylate solution are now allowed to slowly flow in from separate storage vessels. The mixture is stirred for a further 30 minutes at -10.degree. C. and for 2 hours at + 20.degree. 110 parts of 10% sulfuric acid are then added. An oil precipitates out and is extracted with petroleum ether. The petroleum ether extracts are washed with water, dried with sodium sulfate at + 5 ° C. for 12 hours and filtered. The filtrate is filtered through a column with aluminum oxide (activity 2 according to Brockmann) and freed from petroleum ether by distillation. The residue is distilled in a high vacuum. About 40 parts of starting material of the formula V are recovered. 55 parts of axerophthene (deoxyvitamin A), which slowly crystallize on standing at low temperature and after recrystallization from acetonitrile, show a melting point of 75 to 76 ° C, distil 55 parts of axerophthene (deoxyvitamin A) at b.p.a.QOS = 135 to 140 ° C, R "", 325 ma, E = 48,000 (methanol).

Example 2 100 parts of 5- [2 ', 6', 6'-trimethylcyclohexen- (2 ') -yhden- (1')] -3-methylpentadiene-1,3 (V) are mixed with 180 parts of triphenylphosphine hydrobromide in 200 parts of dimethylformamide Stirred for 6 hours at + 15 ° C. The yellow solution is cooled to -10 ° C and left as Described in Example 1, 80 parts of ß-formylcrotonic acid ethyl ester dissolved in 80 Parts of dimethylformamide and 87 parts of a 30% strength methanolic sodium methylate solution to run slowly. After work-up analogous to that described in Example 1, are 30 parts of unreacted starting material of the formula V and 75 parts of ethyl vitamin A ester obtained from bp o, oo5 = 165 to 170 ° C.

The saponification of the ester obtained in this way provides all-trans-vitamin A acid from m.p. = 178 to 179 ° C, X. "" 351 to 352 my, a = 41,000 (methanol).

Example 3 100 parts of 5- [2 ', 6', 6'-trimethylcyclohexen- (2 ') - ylidene- (1')] -3-methylpentadiene-1,3 (V) are mixed with 150 parts of triphenylphosphine hydrochloride in 200 parts of dimethylformamide Stirred for 24 hours at room temperature, then 60 parts of β-formylcrotonic acid are added to the yellow solution, after cooling to -20 ° C., 242 parts of a 30% methanolic sodium methylate solution are allowed to flow in. The mixture is stirred for a further 4 hours at 0 ° C. and the reaction mixture is then poured onto ice and excess 10% phosphoric acid. The mixture is extracted with ether, the red-yellow ethereal solution is washed with water and extracted with 5% ammonia. The pale brown ammoniacal solution is shaken out several times with ether and then acidified with 10% sulfuric acid while cooling with ice, the vitamin A acid precipitating partly in crystalline form. The precipitated acid is taken up in ether, the yellow ether solution is washed with water, dried over sodium sulfate and the ether is distilled off. The residue is digested with ice-cold methanol and filtered off with suction; 40 parts of vitamin A acid are obtained which, after crystallizing once from methanol, have a melting point of 178 to 179 ° C., / L @ yd 351 to 352 ml, e = 40,000 (methanol). Example 4 200 parts of 5- [2 ', 6', 6'-trimethylcyclohexen- (2 ') - ylidene- (1')] - 3-methylpentadiene-1,3 (V) are mixed with 300 parts of triphenylphosphine hydrochloride in 400 parts of dimethylformamide Stirred for 12 hours at + 10 ° C. 174 parts of a 30% strength methanolic sodium methylate solution and a solution of 160 parts of γ-acetoxy-methylcrotonaldehyde (bp "= 95 to 97 ° C.) in 110 parts of dimethylformamide are now simultaneously added dropwise from two separate storage vessels. The reaction solution is cooled kept at -10 ° C. The mixture is stirred for a further 5 hours at 0 ° C. and then acidified with dilute phosphoric acid. The pale yellow oily suspension is then extracted with petroleum ether. The petroleum ether extract is washed with water, dried with sodium sulfate and filtered and the filtrate is concentrated to a volume of about 400 parts.This petroleum ether extract is filtered through an aluminum oxide column (activity 2 to 3 according to Brockmann) The filtrate is removed from petroleum ether under nitrogen in a vacuum and in a short-path distillation unit at 70.degree. C. and 0.0001 Torr freed from low-boiling components. The remaining residue is 150 parts and shows Z "a" 324 to 325 mg, a = 33,000 (isopropanol) Vitamin A acetate concentrate obtained in this way can be further purified by chromatographic adsorption. 50 parts are dissolved in 75 parts of hexane and chromatographed on aluminum oxide (according to Brockmann activity 3 to 4). After a forerun, which consists essentially of unconverted starting material of the formula V, pure all-trans vitamin A acetate is eluted which, when left to stand in a little methanol, partially crystallizes at - (-5 ° C, mp = 57 to 58 ° C , Amd @ 325 m », a = 47,000 (isopropanol); the yield is 12 parts. EXAMPLE 5 88 parts of vinyl-β-ionol are converted into 300 parts of benzene after 0.1 part of p-toluenesulfonic acid is added in the manner described under Example After the reaction solution has cooled and extracted with sodium bicarbonate solution and water, the benzene is distilled off and the residue is stirred with 106 parts of triphenylphosphine without further purification. A solution of 21 parts of hydrogen chloride gas is added to the paste-like mixture at 0 ° C. under nitrogen in 220 parts of methanol are added dropwise. This reaction solution is stirred for 18 hours at room temperature and then simultaneously with a solution of 32 parts of potassium hydroxide in 150 parts of meth anol was added dropwise at - 15 ° C under nitrogen to a mixture of 68 parts of ß-formylcrotonic acid ethyl ester and 40 parts of methanol. The mixture is then stirred for a further hour at room temperature. The reaction mixture is extracted several times with petroleum ether. The combined petroleum ether extracts are washed neutral with water and dried over sodium sulfate. After the petroleum ether has been distilled off, 49 parts of crude vitamin A acid ethyl ester remain in the residue. (2m " = 353 mu, e = 22,000 in methanol).

Claims (3)

PATENT CLAIMS: 1. Process for the preparation of vitamin A and its biologically active derivatives, characterized in that 5- [2 ', 6', 6'-trimethylcyclohexen- (2 ') - yliden- (1')] - 3- methylpentadiene (1,3) together with triarylphosphine hydrohalides or triarylphosphines in the presence of hydrohalic acids and an unsaturated aldehyde of the general formula in which R is a CH2OH group, an esterified or etherified C H2 O H group, a COO H group, an esterified COOH group, a CH, N (CH3) 2 group or a saturated or unsaturated aliphatic radical, preferably a CH, group, in the presence of acid-binding agents and solvents at -50 to -100 ° C, preferably at 0 ° C, and the reaction products obtained, optionally after the addition of mineral acids, in a customary manner, such as extraction and evaporating the extract, isolated. 2. The method according to claim 1, characterized in that Acid-binding agents are alkali or alkaline earth alcoholates or alkali or alkaline earth metal hydroxides used. 3. The method according to claim 1 and 2, characterized in that as Triarylphosphine hydrohalide triphenylphosphine hydrochloride is used.