DE1044807B - Process for the preparation of 15, 15-dehydrocarotenoids - Google Patents

Description

The invention relates to a process for the preparation of IS ^ S'-dehydrocarotenoids. The process is characterized in that the known organometallic condensations of acetylene on the one hand with 8- [2 ', 6', 6'-trimethylcyclohexen- (1 ') - yl] -2,6-dimethyloctatrien- (2, 4,6) -al- (1) and on the other hand with an 8- [2 ^ 6 ^ 6'-trimethylcyclohexen- (1 ') - yl] -2,6 which is substituted in the 4'-position by a hydroxyl or an acyloxy group -dimethyloctatriene- (2,4,6) -al- (l) obtained l, 18-di- [2 ', 6', 6'- substituted in a ring in the 4'-position by a hydroxyl or an acyloxy group trimethylcyclohexen- (1 ') - yl] -3,7,12,16-tetramethyl-8,11-dihydroxy-octadecahexaen- (2,4,6,12,14,16) -in- (9), optionally after usual esterification, a usual double water or. Subjected to acid elimination with allyl rearrangement and the 4'-acyloxy derivative obtained, if appropriate, subsequently saponified under alkaline conditions in a manner known per se. For the production of carotenoid compounds are im. Various procedures have become known over the years. However, the various methods are mostly unsuitable for the preparation of carotenoids which are substituted in the cyclohexene ring by hydroxyl or acyloxy groups. So is z. B. that of Karr er and coworkers in HeIv. Chim. Acta, Vol. 33, 1950, pp. 1172 and 1952, the method described is unsuitable because of the uncontrollable elimination of water or acid on the aliphatic chain and in the cyclohexene rings. Surprisingly, however, it is now possible within the scope of the present invention according to what was already described in Liebigs Ann. der Chemie, Vol. 588, 1954, pp. 117 to 125, described construction principle C ₂₁ -j- C ₁₉ = C ₄₀ , to produce the carotenoid compounds substituted in a ring in the 4'-position by hydroxyl or acyloxy groups. In particular, it is astonishing that in this case _{water or acid is split off from the optionally esterified C 40} triol formed as an intermediate only from the non-cyclic middle section, while the oxygen-containing substituents in the cyclohexene ring remain unchanged. The process according to the invention therefore opens the way to the 15,15'-dehydrocarotenoids substituted by hydroxyl or acyloxy groups, which can easily be converted into the corresponding 15,15'-cis and all-trans carotenoids, which were previously hardly accessible synthetically are.

_{The substituted C 19} aldehydes required as starting materials can be prepared, for example, as follows:

S - ^ '. O'.o'-TrimethyW-acetoxycyclohexen-il'J-yl] -2,6-dirnethyloctatriene- (2,4,6) -al- (l)

4- [2 ', 6', 6'-trimethyl-4'-oxocyclohexylidene] -2-methylbutene- (2) -al- (l) is acetalized, reduced with lithium aluminum hydride and hydrolyzed with acetic acid. That obtained 4- [2 ', 6', 6'-trimethyl-4'-acetoxycyclohexylidene] -

Method of manufacture
from. lS ^ '- Dehydrocarotenoids

Applicant:

F. Hoffmann-La Roche & Co.
Aktiengesellschaft, Basel (Switzerland)

Representative: Dr. G. Schmitt, lawyer ,.
Loerrach (Bad.), Friedrichstr. 3

Claimed priority:
Switzerland from July 22, 1955

Dr. Otto Isler, Dr. Marc Montavon,

Dr. Rudolf Ruegg, Basel,

and Dr. Paul Zeller, Neuallschwil (Switzerland),

have been named as inventors

2-methylbutene- (2) -al- (l) is converted into the enol acetate with isopropenyl acetate, this is saponified and alkaline acetylated, whereby 4- [2 ', 6', 6'-trimethyl-4'-acetoxycyclohexen- (l ') - yl] -2-methylbutene- (2) -al- (l) is obtained. Acetalization, condensation with vinyl ether and hydrolysis with acetic acid give the 6- [2 ', 6', 6'-trimethyl-4 ' -acetoxycyclohexen- (1 ') -yl] -4-m.ethylhexadiene- (2,4) -al- (l), which by acetalization, condensation with Propenyl ether and hydrolysis with acetic acid das

methyloctatriene- (2,4,6) -al- (l) provides.

8- [2 ^ 6 ^ trimethyl-4'-hydroxycyclohexen- (l ') - yl3-2,6-dimethyloctatriene- (2,4,6) -al- (l)

is obtained by boiling 8- [2 ', 6', 6'-trimethyl-4'-acetoxycyclohexen- (l ') - yl] -2,6-dimethyloctatrien- (2,4,6) -al- (l ) with sodium bicarbonate in 90% methanol; UV absorption maximum at 312 παμ. in petroleum ether solution.

The 10-P'.ö'.o'-trimethylcyclohexen- (1 ') -yl] -4,8-dimethyldecatriene- (4,6,8) -in- (1) -oil- (3) - (/ 3-C ₂₁ - acetylene carbinol) can be produced as follows:

The β-C ^ aldehyde is allowed to react in liquid ammonia with an alkali metal or alkaline earth metal acetylide and the condensation is carried out in liquid ammonia under elevated pressure at room temperature or under normal pressure at the boiling point of the ammonia. The /? - C ₁₉ aldehyde is preferably condensed with

■ 809 680/560

3 4

Lithium acetylide, which is treated in the same hydrohalic acid before the reaction. All that is needed is a small vessel and in the same amount of ammonia that for the condensation amount of acid, if the reaction is used by heating, is accelerated from lithium metal and acetylene. One works with advantage in ethyl ether. The / 5-C ₁₉ aldehyde can be added in an inert and using an excess of alcoholic water-chlorinated solvents such as ether. The hydro- 5 hydroic acid. Another suitable method of working consists in lysis of the condensation product succeeds in liquid, that the /? - C ₄₀ diol or one of its esters in ammonia by adding an ammonium salt or a halogenated hydrocarbon with a large dipole after removal of the ammonia by handling with momentary at one temperature below 0 ° C with aqueous acid. The / 3-C ₂₁ -Acetylencarbinol is a viscous hydrohalic acid treated and then from oil, which in the Zerewitinoff determination in the io of the halogen compound formed by the action of cold 1 mol and in the heat 2 mol of active hydrogen water or a basic compound halogen water atoms indicates. In the ultraviolet spectrum, it splits off charac- ter. Teristic absorption maxima are suitable as solvents for this purpose. Methylene chloride and chloroform, as an aqueous halogen, the substituted C 1 -C 4 -acetylenic acid-concentrated aqueous hydrogen bromide carbinol can be prepared in the same way. At the first stage of 15 acid. The process according to the invention is obtained in a ring in the 4'-position, if the substituted IS, 15'-dehydro-jlS-carotm (15,15'-dehydro-obtained jS-Ca-acetylene carbinol with the substituted cryptoxanthine or its ester) is obtained. , which can also be purified in itself by crystallization _{with C 19} aldehydes or the substituted C ₂₁ acetylene partition between solvents, chromatography or carbinols with c _{19 aldehyde.} The 15.15'-decant manner by an organometallic reaction. 20 hydrocryptoxanthinester can be saponified in the man z. B. be converted to the / 3-Ga-acetylene carbinol in a 15,15'-dehydrocryptoxanthin. Last inert solvent 2 moles of alkyl magnesium halide can then act again by esterification into other or 2 moles of phenyl lithium. The first mole of ester will be converted. The saponification takes place in is bound by the hydroxyl group, while in a known manner, for. B. by treating with alkali the second mole with the acetylene bond reacts 25 hydroxides, carbonates or bicarbonates in space and makes the terminal carbon atom reactive at temperature or elevated temperature in the presence of one. The formed dimagnesium halide compound diluent. The esterification takes place in over- or dilithium compound is then set in the same way Licher, for. B. by handling with acid halide solvents with the substituted / JC-Lg aldehyde. or anhydrides in the presence of a tertiary organic base, wi <* pyridine, is expediently used in the substituted /? - C _{19 aldehyde.}

4'-hydroxyl group by esterification, e.g. B. The products of the process are crystalline compounds, acetylation, protected from reaction. Preferably, the absorption maxima at 430 in the ultraviolet spectrum are treated with the / SC ₂₁ -acetylenecarbinol in one and 458 πιμ. in petroleum ether. There are important solvents, such as ether, with 2 moles of alkyl magnesium intermediates for the synthesis of cryptoxanthin halide and condenses the dimagnesium 35 and its esters formed to supplement the technical halide compound without isolation and purification with usefulness. So you can 15,15'-dehydrocryptoxanthin 1 mole of the substituted / SG ^ -aldehyde. The condensation product or its ester partially hydrogenating the triple bond is best hydrolysed without purification in an over- and by heating in an inert solvent Licher way, for example by pouring isomerize, with cryptoxanthin or its ester entin a mixture of ice and dilute sulfuric acid , 40 stand. Cryptoxanthin and its esters are natural, the monosubstituted /? - C ₄₀ diol being obtained. fat-soluble dyes.
The monosubstituted / 3-C ₄₀ -Dk) Ie are very viscous oils,

the absorption example characteristic of the ultraviolet spectrum
exhibit maxima. In the Zerewitinoff determination, they indicate 2 moles of active hydrogen atoms. 45 is passed into a solution of 0.85 parts by weight In the same way, the substituted C ₂₁ -Acetylen- Lithiumin 400 space part liquid ammonia dry carbinols using a an excess of acetone-free acetylene until the lithium completely around Grignard reagent with the j? - C ₁₉ aldehyde is relieved. Then speaking monosubstituted / 3-C ₄₀ -diols are condensed with vigorous stirring. within 20 minutes a solution of 27.8 wt. In the second stage of the process according to the invention 50 divide 8- [2 ', 6', 6 '-trimethylcyclohexen- (1') -yl] -2,6 - the monosubstituted one becomes / 3-C ₄₀ -Dk) I, optionally methyloctatriene- (2,4,6) -al- (l) in 100 parts of space, dry after esterification, to a customary double water or ether and the reaction mixture is stirred with elimination of acid with allyl rearrangement subject. Exclusion of moisture intensively for 20 hours. This is then done, for example, by handling the chloride substituted by an esterified hydroxyl group in a 16 parts by weight ammonium ring in small portions and allowing the ammonia to evaporate. According to / SC ₄₀ -DiOIs with phosphorus oxychloride. in an inert addition of 120 parts by volume of water, the ether layer solvent is separated off in the presence of excess pyridine. The remaining reddish oil is sharply dried in or by heating with a strong organic vacuum. 30 parts by weight of acid, such as p-toluene sulfonic acid, are obtained in toluene. Allylumlage-10- [2 ', 6', 6'-trimethylcyclohexen- (l ') -yl] -4,8-dimethylrung and water or acid elimination succeed at the same time-60 decatrien- (4,6,8) -in - (l) -ol- (3); UV absorption maxima early due to the action of aqueous or water at 280.5 and 291 ταμ. (in petroleum ether). This product of free hydrohalic acid. It is expedient that this is dissolved in 200 parts by weight of absolute ether and _{esterified to monosubstituted / SC 40} -DJoI first, for example a solution of ethyhnagnesium bromide, prepared from wise by treating with an acid anhydride or 5 parts by weight of magnesium and 20 parts by weight of ethyl halide in the presence of a tertiary organic base, 65 bromide in 200 parts of absolute ether, under ice like pyridine, whereupon 2 mol of cooling were added dropwise from the esterification product. The mixture will then be split off under cool acid. A suitable working stirring for 1 hour on the reflux condenser in a nitrogen manner consists in boiling a solution of the /? - C ₄₀ diol in the atmosphere. Now, while stirring vigorously or one of its esters in an inert solvent, quickly add 27 parts by weight of 8- [2 ', 6', 6'-trimethyl such as ether, methylene chloride, dioxane, with anhydrous 70 4'-acetoxycyclohexene (l ') -yl] -2,6-dimethyloctatriene-

(2,4,6) -al- (l) in 200 parts by volume of absolute benzene and the mixture is refluxed for 3 hours. The reaction mixture is then poured onto ice water and a little dilute sulfuric acid. The upper layer is washed with water, dilute sodium bicarbonate solution and water. After drying and evaporation of the solvent, the crude l- [2 ', 6', 6'-trimethylcyclohexene-il'J-yy-lS-P'.ö'.o'-trimethyl ^ '- acetoxycyclohexen- (Γ ) -yl] -S ^^. lo-tetramethyl-S.ll -dihydroxyoctadecahexaen- (2,4,6,12,14,16) -in- (9) dissolved in 1050 parts by volume of methylene chloride and 40 parts by volume of glacial acetic acid. Is then added at - 40 ⁰ C within 20 seconds 41 parts by volume of 6O ° / o hydrobromic acid, the mixture is stirred vigorously I ¹ Z ₂ minutes at -35 ° C gives 1050 parts by volume of water and stirred for 3 hours at 0 to 3 ° C. The methylene chloride solution is then washed neutral with water, dried with sodium sulfate and evaporated. The residue is shaken with 600 parts by volume of methanol, 400 parts by volume of ether and 60 parts by weight of potassium hydroxide for 12 hours in a nitrogen atmosphere. The reaction mixture is then diluted with 3000 parts by volume of water and 400 parts by volume of ether and the ethereal solution is washed neutral with water. The crude 15,15'-dehydrocryptoxanthin obtained after drying and evaporation (UV absorption maxima at 430 and 458 ηιμ) is purified by chromatography on a hundred times the amount of aluminum oxide (according to Brockmann, activity level II) and recrystallized from methylene chloride-methanol or petroleum ether.

Claims (1)

Claim: Process for the preparation of 15,15'-dehydrocarotenoids, characterized in that the by known organometallic condensations of acetylene on the one hand with 8- [2 ', 6', 6'-trimethylcyclohexen- (l ') - yl] -2,6-dimethyloctatrien- (2,4,6) -al- (l) and on the other hand with one substituted in the 4'-position by a hydroxyl or an acyloxy group S-ß'.o '^' - trimethylcyclohexen- (l'j -yl] -2,6-dimethyloctatriene- (2,4,6) -al- (l) obtained in a ring in the 4'-position through a hydroxyl or an acyloxy group substituted l, 18-di- [2 ', 6', 6'-trimethylcyclohexene (1 ') -yl] -3,7,12,16-tetramethyl-8,11 -dihydroxyoctadecahexaen- (2,4,6,12,14,16) -in- (9), optionally after customary esterification, a customary double elimination of water or acid with allyl rearrangement and the 4'-acyloxy derivative obtained, optionally then in a manner known per se alkaline saponified. Considered publications:
German Patent Nos. 855 399, 823 589;
Liebigs Ann. der Chem., Vol. 570, 1950, pp. 54 to 69; Vol. 594, 1955, pp. 165 to 176; Vol. 588, 1954, pp. 117 to 125; J. Am. Chem. Soc, Vol. 77, 1955, pp. 1053, 1054. © 309 & 80 / 56Q 11.58