DE886601C - Process for the production of vitamin A-effective polyene carbonic acids, their esters, vitamin A alcohols or their esters - Google Patents

Description

Process for the production of vitamin A-effective polyenecarboxylic acids, their esters, vitamin A alcohols and their esters The invention relates to the synthesis of carotenoid-polyene compounds, especially those that have a Have vitamin A effects.

Substances active in vitamin A are characterized by the polyene group of the formula Substances active in vitamin A are vitamin A acids, esters, ethers and alcohols that contain this polyene group. The synthesis of such conjugated polyenes is made more difficult by the tendency of these compounds to unpleasant decomposition and undesired side reactions.

The well-known ß-ionon has the following formula: in which R is a 2, 6, 6-trimethyl-cyclohexanol radical. The double bond in the ring of the ß-ion is conjugated with the unsaturated side chain as in vitamin A substances. In a preferred process for the synthesis of vitamin A, ß-ionone is converted into ß-ionylidene acetaldehyde, namely first ß-ionone is converted into the ß-ionylideneacetic acid ester, which is reduced to ß-ionylidene ethanol and then to ß-ionylidene. acetaldehyde is oxidized. According to the invention, ß-ionylidene acetaldehyde is then condensed with an ester of ß-methylglutaconic acid to give an α, γ-dicarboxylic acid which corresponds in its chemical composition to a vitamin A dicarboxylic acid and has the following structure This dicarboxylic acid is then decarboxylated to the corresponding α-monocarboxylic acid, which as a rule consists at least partially of the cis isomer. It should be noted that vitamin A-active substances occur both as cis and as trans isomers. Natural vitamin A esters and the vitamin A alcohol derived from them by saponification consist mainly of the trans isomer and the smaller part of the cis isomer. Both isomers show biological vitamin A activity.

The monocarboxylic acid is in the corresponding alcohol or in the Converted to ester. The alcohol is produced by reducing the monocarboxylic acid or their esters. Vitamin A esters are preferably made by esterifying the alcohol manufactured. It is sometimes desirable to have a vitamin A active compound predominantly in the trans form. The isomerization of at least part of the cis isomer the trans isomer easily becomes by heating the monocarboxylic acid, the ester or Alcohol under reflux in an organic solvent, preferably in the presence an isomerization catalyst, e.g. B. iodine, acid salts and the like.

A preferred process for converting ß-ionone into ß-jonylideneacetic ester consists in that ß-ionone with a haloacetic ester in the presence of a Reformatzky catalyst implemented and hydrolyzed to ß-ionol-acetic acid ester and this to ß-ionylideneacetic acid ester becoming dehydrated. Chlorine, bromine and iodoacetic esters are used as halogen acid esters preferred to fluoroacetic esters. ' Alkyl haloacetic esters, such as methyl, ethyl, propyl and like alkyl haloacetic esters, are also suitable for reaction, though other aliphatic and aromatic haloacetic esters can also be used. The reaction takes place in the presence of a Reformatzky catalyst; H. of an active Metal, such as zinc or magnesium, whereby an organometallic compound is formed, which by hydrolysis in an acidic medium into the corresponding oxyester, the ß-ionolacetic acid ester, is converted. The oxyester then becomes the desired β-jonylideneacetic acid ester by heating or, even more advantageously, in the presence of a dehydrating catalyst, z. B. iodine, phosphorus oxychloride, phosphorus trichloride, oxalyl chloride, mineral acids, acidic salts, acidic earths or the like, dehydrated.

The ß-Jonyliden-acetic acid ester is then reduced to -ß-Jonyliden-ethanol. The reduction of the ester to the alcohol is expediently effected in the presence of an ether-soluble metal hydride such as aluminum hydride, lithium aluminum hydride or lithium borohydride, the remaining double bonds being retained.

ß-Jonyliden-ethanol is then oxidized to ß-Jonylidenacetaldehyd. The oxidation is effected with finely divided manganese dioxide. Oxidation can also in the presence of acetone or diethyl ketone or aniline with aluminum isopropylate take place.

The ß-Jonyliden-acetaldehyde is then with ß-Methyl-glutaconsäureester condensed to the α, γ-dicarboxylic acid. The condensation takes place in the presence of a basic condensation agent, usually the condensation product at least is partially saponified to the α, γ-dicarboxylic acid. In another condensation will then completely saponified.

As ß-methyl-glutaconic acid ester, the methyl, ethyl, propyl, Butyl or similar alkyl esters, aryl and aralkyl esters, such as phenyl or benzyl esters, be used.

Strong bases are expediently used for the condensation, such as alkali hydroxides, Alcoholates, ammonium hydroxide, substituted ammonium hydroxides, alkali metals, alkali hydrides, Alkali amides and others, e.g. B. Sodium hydroxide, potassium hydroxide, sodium ethylate, sodium methylate, Tetramethylammonium hydroxide, tetraethylammonium hydroxide, potassium hydride, sodium amide, Potassium amide, lithium amide.

The condensation of ß-Jonyliden-acetaldehyde with the ß-Methyl-glutaconsäureester is preferably carried out in a solvent. Preferred solvents are Alcohols, ethers, benzene, toluene and similar known solvents. When the condensing agent a. Alkali metal, alkali hydride or amide is preferably ether or benzene used. Alcohols such as methanol, ethanol, propanol, isopropanol and the like are used preferably used with hydroxides, alcoholates and ammonium hydroxides.

The a, y-dicarboxylic acid is then decarboxylated, reduced, isomerized or esterified. Complete decarboxylation of the α, γ-dicarboxylic acid gives a polyhydrocarbon. The dicarboxylic acid expediently becomes the α-monocarboxylic acid decarboxylated, which chemically corresponds to vitamin A acid. Decarboxylation can be effected by merely heating the dicarboxylic acid, for example to a temperature above zoo °. The decarboxylation to γ-monocarboxylic acid takes place preferably by heating in the presence of an organic base, preferably a trivalent amine and a finely divided metal, metal salt or metal oxide. Suitable organic bases are pyridine, quinoline, triethylamine and diethylamine. Suitable metallic catalysts are copper powder, copper-bronze powder, Copper oxide, copper chromite, copper acetate, copper sulfate. The decarboxylation takes place preferably at a temperature of about go to z75 ', although they are also at lower temperatures, such as about 60 'or even lower, or at temperatures over i75 ', e.g. at Zoo' or higher, depending on the reaction time, can be performed, which takes about 15 minutes to about 3 hours will.

It is convenient to carry out the decarboxylation under such conditions execute that only the monocarboxylic acid is formed in a mixture with the dicarboxylic acid. This is better than having more severe conditions requiring complete decarboxylation a part of the dicarboxylic acid can be used. The monocarboxylic acid is then separated from the dicarboxylic acid and recovered for further treatment. The degree of decarboxylation can be known by determining the level of carbon dioxide Way to be measured.

The monocarboxylic acid can then be reduced immediately to vitamin A alcohol are treated with an ether-soluble metal hydride, such as aluminum hydride, Lithium aluminum hydride or lithium borohydride. However, the α-monocarboxylic acid is preferred esterified. The esterification should take place without shifting the double bonds. The monocarboxylic acid is treated in methyl ethyl ketone with an alkyl halide in Presence of an alkali carbonate, preferably an alkali halide. Under these Conditions, the dicarboxylic acid does not esterify in a mixture with the monocarboxylic acid, and the dicarboxylic acid can be easily separated from the monocarboxylic acid, for example by chromatography, extraction with a solvent, fractional crystallization or similar separation processes.

The reduction of the vitamin A acid ester to vitamin A alcohol becomes easily effected by treating the esters with an ether-soluble metal hydride. If necessary, the vitamin A alcohol can then be mixed with a carboxylic acid or an acyl halide.

The following examples illustrate the method according to the invention. Example 96 g of β-ionone, 96 g of ethyl bromoacetate, 37.6 g of zinc foil, 250 cc of benzene and an iodine crystal were mixed and refluxed until the reaction began. The heat of reaction maintained the reflux, after which the mixture was refluxed for a further 30 minutes heated. The reaction mixture was cooled, shaken with an excess of 5% hydrochloric acid, the benzene layer deposited and washed successively with water and dilute sodium carbonate solution. The benzene layer was then dried over sodium sulfate and the benzene evaporated. The residue was distilled in a high vacuum, whereby f $ - Jonol-acetic acid ethyl ester was obtained as a pale yellow, viscous oil; E I2 2 m (23i mu) = 200.

48 g of ß-ionol-acetic acid ethyl ester were dissolved in 65 cc of benzene, a small iodine crystal was added and the mixture was heated under reflux for 30 minutes. The benzene solution was washed successively with dilute sodium thiosulfate and water, dried and the solvent evaporated. After purification, a mixture of α, β-unsaturated β-ionylidene-acetic acid ethyl ester and the β, γ-unsaturated isomer with an absorption maximum at 284 μm is obtained.

The elimination of water and the simultaneous isomerization of part of the ß, γ-unsaturated isomer takes place according to the following process: 14.8 g of ß-ionol-acetic acid ethyl ester were dissolved in 10 6 cc of benzene and mixed with 0.5 cc of phosphorus oxychloride dissolved in 42 cc of benzene . This mixture was refluxed for 1 hour, then cooled, chromatographed over 15 g of sodium aluminum silicate and eluted with 100 cc of benzo. After the benzene had been removed in vacuo, the residue was dissolved in 100 cc of petroleum ether and chromatographed on a column of finely divided sodium aluminum silicate. The column was then washed with 100 cc of petroleum ether and the extracts evaporated, 8 g of ß-jonylideneacetic acid ethyl ester with E '# 1 .. (256 mu) = 45o and E (304 mu) = 552 remaining. The column was then washed with 1300 cc of acetone in order to obtain the ß, γ-unsaturated isomer of ß-Jonyliden-acetic acid ethyl ester. The acetone was evaporated to give 6.5 g of β, γ-unsaturated isomer. This was dissolved in 35 cc of benzene and 0.2 l cc of phosphorus oxychloride in 30 cc of benzene was added. The mixture was refluxed for 6 hours, cooled, washed repeatedly with water, dried over sodium sulfate, filtered and the solvent evaporated. The residue consisted of 6.4 g of a mixture of ß-Jonyliden-acetic acid ethyl ester and the ß, γ-unsaturated isomer. It was dissolved in 50 cc of petroleum ether and passed through an absorption column as before. After the column had been washed out with 600 cc of petroleum ether, the ether fractions were combined and the solvent was evaporated, 3 g of ß-jonylideneacetic acid ethyl ester remaining. The further separation and re-treatment of the β, γ-unsaturated isomer resulted in an essentially complete conversion into the α, ß-unsaturated ß-jonylideneacetic acid ethyl ester.

4.6 g of ß-ionylideneacetic acid ethyl ester are dissolved in 60 cc of dry ether and 50 cc of a 0.4 N ethereal solution of lithium aluminum hydride are added over the course of 2 minutes. The mixture was stirred for 5 minutes, with zoo cc 5% hydrochloric acid diluted, the ether layer washed with water, dried with sodium sulfate and the solvent evaporated, whereby 4 g ß-Jonylidenethanol were obtained; E1 C. (265 mp) = 534 (in ethanol). 0.5 g ß- Jonylidene ethanol was dissolved in 3 cc of dry benzene containing 0.75 g of tert-aluminum butylate and = cc of aniline. 2 cc of diethyl ketone were added to this mixture and heated under reflux for 16 hours at 100 °. The reaction product was 30 cc 5 ° / Hydrochloric acid and extracted with ether. The ether extract was washed successively with dilute hydrochloric acid, 5% sodium bicarbonate solution and water and dried with sodium sulfate. The solvent was evaporated, whereby 0, 48 g of β-ionylidene acetaldehyde were obtained. After purification by chromatography, the product had Ei @ m (272 mu) = 540 and E'1 ', "(326 mu) = 676. The 2,4-dinitrophenylhydrazone of the aldehyde melted at 198 to 200 ° and had Ei m ( 4o5 MM) = 990.

Manganese dioxide is particularly advantageously used as the oxidizing agent for the oxidation of β-ionylidene ethanol to β-ionylidene acetaldehyde. 30 g of β-ionylidene ethanol with a purity of 85% (E1.15 (267 mcc) = 516) were dissolved in 300 cc of methylene chloride and 79 g of finely powdered manganese dioxide were added. The mixture was left to stand at 25 ° for 22 hours, filtered to separate off the manganese dioxide and the solvent was evaporated. 27.9 g of β-ionylidene acetaldehyde are obtained; Ei ,, m (326 mA = 407.

5 g of ß-methyl-glutaconic acid ethyl ester, 5 g of ß-ionylidene acetaldehyde and 2.5 g of potassium hydroxide dissolved in 100 cc of methyl alcohol were mixed and the mixture was left to stand for 2 days at room temperature. The alcohol was then distilled off under reduced pressure, the residue acidified with dilute hydrochloric acid and extracted with ether. The ether extract was washed with water and extracted with 50 cc and then twice with 25 cc of 8% sodium hydroxide. The extracts were combined, acidified with hydrochloric acid and the condensation product separated therefrom. This was heated under reflux for 45 minutes with 5.6 g of potassium hydroxide in 16 cc of water and 2o cc of ethyl alcohol and saponified, extracted with ether and the extract acidified, whereby 7.4 g of the α, γ-dicarboxylic acid in the form of a yellow, solid Mass received. The dicarboxylic acid was recrystallized from dilute alcohol and petroleum ether-acetone, resulting in a pale yellow, solid mass with a melting point of 186 to 189 ° and Eilur (333 ml4) = 810 .

The condensation of the ß-ionylidene acetaldehyde with ß-methyl-glutaconic acid ester can also be brought about with a basic condensing agent. It is z. B. to a solution of 1.7 g of ß-methyl-glutaconic acid ethyl ester in 15 cc of anhydrous ether containing 0.5 cc of ethyl alcohol, 0.23 g of metallic sodium added. The solution is stirred for 1 hour and a solution of 2.75 g of β-ionylidene acetaldehyde (80 ° / ° purity) in 10 ccm of ether is added and, after stirring for a further 20 minutes, 1 cc of glacial acetic acid is added, the mixture is poured into water and the ether layer is added deducted. This was then washed with a 0.5N potassium hydroxide solution and acidified. The acidified mixture was extracted with ether, the extract washed with water, dried and the ether evaporated from the extract. The residue was saponified with 2N potassium hydroxide and 1.35 g of the dicarboxylic acid were separated off. After precipitation from an ethyl ether solution by adding petroleum ether, the dicarboxylic acid had the form of a yellow, solid mass, E i 1 (333 ma) = 863 and a melting point of 186 to z89 °, measured in the Fisher-Johns device.

A mixture of 3.4 g of dicarboxylic acid and 12 cc of quinoline was 40 Heated to 15o to 16o ° for minutes. The mixture was then cooled, acidified and undressed with ether. The ether extract was then treated with 4% aqueous sodium hydroxide pulled out and the basic extract acidified, resulting in a reddish-brown, brittle, glassy mass resulted. This was then recrystallized from alcohol, whereby reddish brown prismatic crystals of the monocarboxylic acid resulted, the one Melting point from 169 to 27o.5 ° and egg ', (352 mu) = 228o.

However, the decarboxylation can also be carried out in the presence of a tertiary amine, copper powder or a copper compound. A solution of 2, oga, γ-dicarboxylic acid (Eigiro (333 mA) = 863) in 10 cc of pyridine, which contained 0.1 g of copper powder, is refluxed for 1 1/2 hours. The solution was cooled, diluted with 50 cc of ether and washed successively with 5% hydrochloric acid, water and 0.5 N potassium hydroxide. The alkali solution was separated off, acidified with dilute hydrochloric acid and the monocarboxylic acid extracted with ether. The ether extract was washed, dried and the ether evaporated. After crystallization, the residue had egg @m (353 mu) = 1300- 0.25 g of the monocarboxylic acid was dissolved in 50 cc of benzene containing 0.3 mg of iodine. The solution was exposed to sunlight at room temperature for 3 hours and then filtered through a column of finely powdered sodium thiosulfate to remove the iodine. The solvent was evaporated. The residue obtained was E111.5. (24o MM = 248 and El @ m (35o mu) = 151o, which corresponds to a6, 40 /,) the trans form of vitamin A acid.

4 cc of a 1 molar solution of lithium aluminum hydride in ether were added to a solution of 0.5 g of the monocarboxylic acid in 50 cc of anhydrous ether. The solution was refluxed gently for 3 minutes and the excess lithium aluminum hydride was destroyed with dilute hydrochloric acid. The ether solution was washed successively with 5% hydrochloric acid, 0.5 N potassium hydroxide and water, dried, filtered and the ether evaporated. 0.47 g of yellow oily vitamin A alcohol were obtained; EI '.. (326 mA) = 1215. A colorimetric test with antimony trichloride showed an effectiveness of 1,930,000 units of vitamin A per gram. This value was confirmed by biological testing.

10 g of vitamin A monocarboxylic acid were refluxed to 70 to 75 ° in 48 cc of methyl ethyl ketone, 6.7 cc of ethyl bromide, 2.4 g of potassium carbonate and 0.03 g of sodium iodide. The methyl ethyl acetate was evaporated and the carbonate was decomposed by the addition of dilute hydrochloric acid. The ethyl ester was extracted with isopropyl ether and the ether evaporated. zo g of ethyl ester were dissolved in 38 cc of anhydrous ethyl ether, and 1.2 g of lithium aluminum hydride, dissolved in 65 cc of anhydrous ether, was slowly added to the solution. Within 5 minutes of starting the addition of the metal hydride, the reaction mixture was diluted with water to destroy the excess metal hydride. The reaction product was then washed successively with dilute hydrochloric acid, 4% aqueous sodium bicarbonate and water. The vitamin A alcohol obtained had a vitamin A effect of 1,650,000 units per gram.

A solution of 0.5 g of cis-vitamin A alcohol in refined cottonseed oil was mixed with 2 cc of benzene containing 0.2 mg of iodine. The mixture was allowed to stand at room temperature for 2 hours. The iodine was removed with sodium thiosulfate and the solvent evaporated. The chemical test showed a ratio of trans-vitamin A alcohol: cis vitamin A alcohol of 82:18 .

Zg of the cis-vitamin A palmitate, Eid, (328 mu) = 615, was dissolved in 10 cc of benzene containing 2.5 mg of iodine. The solution was left to stand for 45 minutes at room temperature, the iodine was removed with sodium thiosulfate and the solvent was evaporated. The chemical test showed a ratio of 68:32 of the trans-vitamin A palmitate: cis-vitamin A palmitate. The procedure was repeated using 5 mg of iodine for a reaction time of 2 hours. The trans: cis ratio was then 88:12 .

Claims (3)

PATENT CLAIMS: e.g. Process for the production of vitamin A effective Polyenecarboxylic acids, their esters, vitamin A alcohols or their esters, thereby characterized in that manß-ionone with a haloacetic ester or its alkyl derivatives according to Reformatzky, subsequent hydrolysis and elimination of water in the ß-Jonylidenessigsäureester transferred, this reduced with an ether-soluble metal hydride to ß-Jonylidenäthanol, thiszum-jonylidene acetaldehyde is oxidized, which is formed with ß-methylglutaconic acid esters in Presence of basic catalysts for the dicarboxylic acid with simultaneous or subsequent Saponification is condensed, the dicarboxylic acid to the corresponding monocarboxylic acid decarboxylated and this either esterified or reduced to polyene alcohol, the can optionally be esterified and isomerized. 2. The method according to claim z, characterized in that the monocarboxylic acid ester with ether-soluble metal hydrides is reduced to the corresponding alcohol. 3. The method according to claim x, characterized characterized in that the decarboxylation of the dicarboxylic acid in the presence of an organic Base and a copper compound takes place.