DE1068709B - Process for the synthesis of compounds of the axerophthalene series - Google Patents

Description

The axerophthylidene residue (I) is characterized by the carbon structure of vitamin A and its position of the double bonds, especially the one in ^ position im Ring:

CH ₃ CH ₃

c-

/ \ 7 fl Q m 11 19 - t! υ ις

C-CH = CH-C = CH-CH = CH-C = CH-Ch = "

IO

H ₂ CC

CH.

CH,

Cxi2 CrIg

Method of synthesis

of connections
the Axerophthyliden series

Applicant:

Aniline & Soda Factory in Baden

Corporation,

Ludwigshafen / Rhine

Of the few known compounds of the axerophthylidene series, the carotenes are the most important. Process for the production of compounds of the Axerö ao phthyliden series from vitamin A or its dehydration product, Anhydrovitamin A does not yet exist.

It has now been found that compounds of the axerophthylidene series are obtained if vitamin A (II) or anhydrovitamin A (III)

CH,

CH,

II

[-H ₂ O]

CH-CH = C-CH = CH-CH = C-CH = Ch ₉

Dr. Horst Pommer and Dr. Wilhelm Sarnecki,

Ludwigshafen / Rhine,
have been named as inventors

CH,

CH,

III

with a triarylphosphine and a proton donor or with a hydrosalt of a triarylphosphine on the one hand and on the other hand reacts with an oxo compound with the mediation of a proton acceptor.

The vitamin A used as the starting material can be of natural or synthetic origin. The anhydrovitamin A can either be built up completely synthetically (compare e.g. British patent specification 753 157) or can easily be obtained from vitamin A by treatment with acids (compare e.g. O. Isler and co-workers, HeIv. CMm. Acta, Vol. 30, 1947, p. 1927).

Inorganic acids, in particular the hydrohalic acids, are primarily suitable as proton donors and the oxo acids of sulfur. In addition, all such acids are suitable as those with triarylphosphines Type i salts

CH = CH-C = CH-CH = CH-C = CH-CH ₉ Oh

^R \

R-PH

form (R stands for identical or different aromatic radicals). Χ ^Θ stands for the remainder of an inorganic or strong organic acid, e.g. B. benzenesulfonic acid or trichloroacetic acid.

Examples of the many oxo compounds suitable for the implementation are: acetaldehyde, acrolein, tiglinaldehyde, ^ -Methylcrotonaldehyde, a-methylhexadienal, 2,6-dimethyloctatriene- (2,4,6) -al- (l), _i ff- Methyl crotonic acid, / I-methyl crotonic acid ester, γ-acetoxytiglic aldehyde, γ-alkoxytiglin aldehyde, α-methyl-γ-ethoxyacrolein, 7-carboxy-2,6-dimethylheptatriene- (2,4,6) -al- (1), 8 -Alkoxy-2,6-dimethyloctatriene- (2,4,6) -al- (1), 7-carbalko3y-2,6-dmethy] heptatriene- (2,4,6) -al- (1), 8 -Acetoxy-2,6-dimethyloctatriene- (2,4,6) -al- (l), vitamin A-aldehyde, g-p'.o'.o'-trimethylcyclohexen- (2 ') - yl- ( l ')] - 3,7-dimethylnonatetraen- (2,4,6,8) -al- (l) and 3,7,11,15-tetramethylhexadecahexaen- (2,4,6,8,10,14) -al- (1); even

909 648/432

Dialdehydes are suitable. Formic esters are also to be used for the purposes of the procedure according to the invention Oxo compounds to be expected.

Suitable proton acceptors are acid-binding agents, e.g. B. alkali hydroxides, alkaline earth hydroxides, alkali and alkaline earth amides, alkali and alkaline earth enolates of ketones, ammonia, strongly basic amines, alkali and alkaline earth alcoholates and also organometallic compounds, z. B. Lithium methyl, sodium methyl, phenyl sodium, PhenyUithium, ButyUithium, Natriumacetyhd, Indenyl potassium and Grignard compounds such as ethyl magnesium bromide.

The reaction is advantageously carried out in solvents that can be used in accordance with the oxo compound, the proton donor and acceptor. For example, ethers such as Tetrahydrofuran, dimethyltetfahydrofuran, dioxane, hydrocarbons such as benzene, toluene, xylene, cyclohexane, Cyclooctane, isooctane, alcohols such as methanol, ethanol, isopropanol, propanol, butanol and benzyl alcohol, Fatty acid esters, such as ethyl acetate, butyl acetate. Strongly polar solvents are preferred, such as Nitrobenzene, dimethylformamide, acetonitrile and N-methylpyrrolidone. It is not necessary in all cases avoid the presence of water.

The reaction temperatures can be in wide limits, for example from ⁰ C to +100 -SO be varied and will depend inter alia on the melting point or boiling point of the solvent. In general, it is advantageous to work at temperatures around 0 ^° C.

The quantitative ratio of the reaction components is advantageously chosen to be approximately stoichiometric, although an excess or Deficiency of one or the other component generally affects the desired course of the reaction not bother. An excess of the proton acceptor can be particularly advantageous when acidic groups containing oxo compounds are to be reacted or if the proton donor is in excess applied ".

The yields can still be improved if the reaction mixture is subjected to an inert reaction or better by an inert gas, e.g. B. nitrogen or argon, protects against ingress of atmospheric oxygen.

The mechanism of the new reaction has not yet been fully clarified. Because it is known that vitamin A (II) is extremely easily converted into anhydrovitamin A (III) by treatment with acids but assume that when using vitamin A as a starting material, anhydrovitamin A is formed first, which then reacts in the desired way. However, this assumption is not experimentally secured, and it cannot yet be ruled out with certainty that when choosing anhydrovitamin A and vitamin A as Starting material two mutually different reaction mechanisms take place, both of which result in an unstable one lead in substance not isolated intermediate product of the same constitution. This as yet unknown intermediate would then have to be regarded as the actual starting material of the new synthesis.

The new reaction will be explained using formulas for two particularly characteristic applications. Included is triphenylphosphine as triarylphosphine, hydrochloric acid as proton donor, and as proton acceptor Sodium methylate and dimethylformamide selected as solvent:

A new, valuable, physiologically effective bioaffine dye is obtained, the homobisisoprenovitamin A-acid ethyl ester (V) by reacting vitamin A (II) with y-carbethoxy ^ .ö-dimethylheptatriene- (2,4,6) -al- (l) (IV).

H ₃ C.
\ C.
I. C.
\ CH ₃ \ I.
C.
\ H ₂ H ₂ \
C-CH
Il Il
C.
/ ^N
CH ₂ \
CH ₃

- CH = CH - C = CH - CH = CH - C = CH - CH ₉ - 0H

CH,

CH _a

II

-C = Ch-CH = CH-C = CH-COOC ₂ H

₂ H ₅

CH,

CH ₃

+ (C _e H ₅ ) ₃ P + HCl
in dimethylformamide
+ After ₃

C — CH = CH-C = CH-CH = CH-C = CH-CH = CH-C = CH-CH = CH- C = CH-COOC ₂ H,

CH,

CH,

CH,

CH,

CH »CH,

+ (C ₆ H ₅ ) ₃ PO + NaCl + CH ₃ OH + H ₂ O

5 6

The jÖ-carotene (VII) is obtained z. B. by converting anhydro vitamin A. (III) with vitamin A-aidehyd (VI),

Hq C C Hq

H ₂ CC = CH-CH = C-CH = CH-CH = C-CH = Ch ₂ III

ΧΛ.2 CC CHg

\ / \ CH CH,

H, C

CH,

CH ₃

H ₂ CC-CH = CH-C = CH-CH = CH-C = CH-CHO

I Il _. I ■ ■ I

H2 OC C Hg C < Ed

IV

C Hn C Hq

+ (C ₆ Hs) ₃ P + HCl
in dimethylformamide
+ After ₃

H ₂ C
H, C

= CH - C = CH-

CH,

CH,

H ₃ C CH ₃

CH = CH - CH = C - CH = CH - CH = C - CH = CH - C.

VII

CH, CH,

+ (C ₆ Hg) ₃ PO + NaCl + CH ₃ OH

H ₃ C

CH ₉

At the point of connection (carbon atom 15), the new double bond is initially formed as a mixture of the ice, trans isomers from. Subsequent treatment with isomerizing agents, e.g. B. with halogens, Light of a certain wavelength or acids, the resulting cis.trans isomer mixtures can usually be easily extracted rearrange in connections of the alltrans series.

The compounds of the axerophthylidene series obtainable by the new process are used as pharmaceuticals and used as food coloring.

The parts mentioned in the exemplary embodiments are parts by weight. These are related to the ones mentioned Parts by volume such as kilograms to liters.

example 1

36 parts of triphenylphosphine hydrochloride are slowly added to a solution, cooled to 0 ° C., of 30 parts of vitamin A alcohol in 150 parts by volume of dimethylformamide; the mixture is stirred at 0 ° C. for about 8 hours until a clear, yellow-red solution is obtained. A solution of 14 parts of ß-formylcrotonic acid ethyl ester in 50 parts by volume of dimethylformamide and an approximately 30% solution of 8 parts of sodium methylate in methanol are now slowly run in from two separate storage vessels - for about 30 minutes. The mixture is stirred for a further 3 hours at ⁰ ° C. and 1 hour at room temperature, then covered with a layer of petroleum ether and 10% strength aqueous sulfuric acid is added until the reaction is acidic. After thorough mixing, the orange-yellow petroleum ether solution is separated off and shaken twice more with petroleum ether. The combined petroleum ether extracts are washed with water and, after drying over sodium sulfate, evaporated to dryness in vacuo. An orange-red oil is obtained which partially crystallizes when a little isopropanol is added. The crystals are recrystallized from isopropanol. 17 parts of 13- [2 ', 6', o'-trimethylcyclohexen- (1 ') -yl- (1')] -3,7,11 -trimethyltridecahexaen- (2,4,6,8,10, 12) acid (l) ethyl ester (homoisoprenovitamin A acid ethyl ester) in the form of bright orange-red leaflets with a melting point of 111 ° C, l _max (methanol) 399 ΐημ, ε = 73,000.

With antimony trichloride in chloroform, there is a green color reaction that slowly turns blue.

Example 2

Suspending 28 parts anhydrovitamin together with 36 parts Triphenylphosphinhydrochlorid in 130 parts by volume of dimethylformamide and the mixture is stirred for 12 hours at + 10 ° C. At the then clear yellow-red solution is cooled to 0 ⁰ C, allowed of two separate storage vessels simultaneously 14 parts of ethyl formylcrotonate, dissolved in 50 parts by volume of dimethylformamide, and an approximately 30% solution

run in of 8 parts of sodium methylate in methanol. Proceed as described in Example 1. Man receives 14.5 parts of homoisoprenovitamin A-acid ethyl ester from F. lirC.

Example 3

A solution of 3.6 parts of hydrochloric acid gas in 40 parts by volume of methanol (HCl content determined by titration) is slowly added dropwise to the solution, kept ^{at 0 ° C., of 30 parts of vitamin A alcohol and 26 parts of triphenylphosphine in 100 parts by volume of dimethylformamide.} The mixture is stirred for 12 hours at + 5 ⁰ C and add 10 parts of trans-jS-Formylcrotonsäure (F. 66 ° C, obtained by alkaline hydrolysis of the Diäthylacetals of ß-Formylcrotonsäureäthylesters and Entacetalisierung of the reaction product) is added. The mixture is cooled to - from 5 ° C and quickly adds about a 30 ⁰ / "by weight solution of 20 parts of sodium methylate in methanol. A violent exothermic reaction ensues. The mixture is stirred for a further 15 minutes at room temperature, ao 40 parts by volume of isopropanol are added and the mixture is acidified with 10% sulfuric acid until the Congo acidic reaction occurs. The mixture is stirred for a further 2 hours at room temperature and the orange-red crystals which have precipitated are worked up. 13 parts of IS-P'.o'.o'-trimethylcyclohexen ^ l ') - yl- (1')] -3,7,11 -trimethyltridecahexaen- (2,4,6,8,10,12) acid (l) (homoisoprenovitamin Α-acid) in the form of fine orange-red needles (after recrystallization from isopropanol), mp 188 to 189 ° C, X _max (hexane) 400 πιμ, ε = 65,000.

Example 4

25 parts of a 60% concentrate of 9- [2 ', 6', 6'-trimethylcyclohexene - (2) -ylidene - (1 ')] -3,7 - dimethylnonatetraen- (1,3,5,7) ( Anhydrovitamin A), 25 parts of triphenylphosphine and 30 parts of methanol are stirred at room temperature under nitrogen. Is added dropwise to the reaction mixture, 50 parts by volume of η 2.2 methanolic sulfuric acid is added, stirred it for 5 hours at room temperature and leave it at the same time with 50 volumes of 2.2 η 4ο methanolic potassium hydroxide solution at 0 ⁰ C under nitrogen to a suspension of 14 parts of 7-carbethoxy -2,6-dimethylheptatriene- (2,4,6) -al- (l) run in 60 parts of methanol. The mixture is then stirred for a further 15 hours at room temperature; 14 parts of the ethyl ester of 17- [2 ', 6', 6'-Triinetliylcyclohexen- (l ') -yl- (l')] - 3.7, l 1, 15-tetramethylheptadecaoctaen- (2,4, 6, 8,10,12,14,16) acid- (l) from. The isolated substance still contains inorganic salts. F. after recrystallization from alcohol: 132 ° C, l _max = 436 πιμ, 462 πιμ; ε _43β = 100 200. The mother liquor contains a further 6 parts of the ester, which can be obtained therefrom by adding water and extracting this mixture with ether.

Example 5

55

90 parts of a 60% concentrate of 9- [2 ', 6', 6'-trimethylcyclohexen- (2 ') -ylidene- (1')] -3,7-dimethyhionatetraene (-l, 3,5,7 ) (Anhydrovitamin A) and 90 parts of triphenylphosphine are stirred with 100 parts of anhydrous alcohol under nitrogen. For this purpose, 70 parts by volume of 5 η alcoholic hydrochloric acid are added dropwise at room temperature. The mixture is stirred for 24 hours and then alcoholic under nitrogen simultaneously with 90 parts by volume of 4N Kaülauge to the solution of 60 parts of vitamin A aldehyde in 60 parts of anhydrous alcohol at 0 ⁰ C dropwise. After stirring for 2 hours, the precipitate is filtered off and, after the addition of 40 parts of water, the filtrate is extracted with cyclohexane. The precipitate is digested with cyclohexane in the presence of some water. He goes into solution. The combined cyclohexane layers are washed with water, dried over sodium sulfate and evaporated in vacuo. The residue is 150 parts. It is recrystallized from benzene-methanol. This gives 35 parts of jS-carotene with a melting point of 176 ° C.

Example 6

75 parts of viamin A alcohol and 90 parts of triphenylphosphine are stirred with 100 parts by volume of anhydrous alcohol under nitrogen. 70 parts by volume of a 5 ml alcoholic hydrochloric acid are then slowly added dropwise at room temperature. The mixture is stirred for 24 hours and the resulting solution is simultaneously added dropwise with 90 parts by volume of a 4 η alcoholic potassium hydroxide solution to a solution of 60 parts of vitamin A aldehyde in 60 parts by volume of anhydrous alcohol. The temperature is kept at 0 ° C. by cooling. After stirring for 2 hours, the resulting deep red precipitate is filtered off. After adding 40 parts by volume of water, the filtrate is extracted with cyclohexane. The filter residue dissolved in benzene is combined with the deep red extract. To obtain the end product, the mixture is washed with water, dried over sodium sulfate and evaporated to dryness. All-trans-β-carotene crystallized from the crude product is obtained by dissolving it in 600 parts by volume of hot benzene and precipitating it with 1200 parts by volume of alcohol; F. 177 to 178 ° C, l _max (hexane) 452 πιμ, (ε = 147,000) and 481 πιμ (ε = 134,000); Yield 97 parts.

Claims (6)

Patent claims: 1. A process for the preparation of compounds of the axerophthylidene series, characterized in that vitamin A or anhydrovitamin A with a triarylphosphine and a proton donor or with a hydrosalt of a triarylphosphine on the one hand and with an oxo compound with the mediation of a proton acceptor on the other hand, expediently in an inert organic Solvent, at about -50 to +100 ⁰ C converts. 2. The method according to claim 1, characterized in that the reaction in dimethylformamide, Acetonitrile or methanol. -3. Method according to claims 1 and 2, characterized in that that he. Inorganic acids, preferably hydrohalic acids, as proton donors, used. 4. The method according to claim 1, 2 and 3, characterized in that the proton acceptor alkali or Alkaline earth alcoholates or hydroxides used. 5. The method according to claim 1 to 4, characterized in that the oxo compound is the / 3-formylcrotonic acid and its esters, tiglinaldehyde, 7-carboxy-2,6-dimethylheptatriene- (2,4,6) -al- (l) and its esters, 2,6-dimethyloctatriene- (2,4,6) -al- (l), vitamin A - aldehyde, 9 - [2 ', 6', 6 '- trimethylcyclohexen- (2') -yl- (1 ')] -3,7-dimethylnonatetraen- (2,4,6,8) -al- ( 1) and 3,7,11,15-tetramethylhexadecahexaen- (2,4,6,8,10,14) -al- (l) are used. 6. The method according to claim 1 to 5, characterized in that all reactions are in the presence an inert gas, preferably argon or nitrogen. © 909 648/432 11.59