DE1081454B - Process for the preparation of 6, 7-dehydro-ª ‰ -apo-3-carotinal - Google Patents

Description

The present invention relates to a process for the preparation of δ-dehydro-ß-apo-S-carotenal, which is characterized in that an acetal of 2-methylpentene- (2) -in- (4) -al- ( l) ( _{hereinafter referred to as C 6} acetal) either in a manner known per se first with 8- [2,6,6-trimethylcyclohexen- (l) -yl] -2,6-dimethyloctatriene- (2,4,6) -al- (l) ( _{hereinafter referred to as /? -C 19} -aldehyde) condenses, the condensation product, if desired after hydrolysis, treated in the usual way with acid, then the aldehyde formed is acetalized in a manner known per se, the acetal per se condensed in a known manner with a vinyl alkyl ether and the ether acetal formed is treated in a manner known per se with acid, or in a manner known per se first with a vinyl alkyl ether and then in a manner known per se with S-poö-trimethylcyclohexen-ilJ-yl] -2,6- dimethyloctatrien- (2,4,6) -al- (l) condensed and the condensation product formed, if desired after hydrolysis, in usual Treated fro way with acid.

As shown by the example of the 1,1-diethyl compound, the C ₆ acetals required as starting materials can, for. B. be prepared as follows: Ethyl orthoformate is condensed with propenyl ether in the presence of boron trifluoride etherate to give 1,1,3,3-tetraethoxy-2-methylpropane (boiling point b.p. _lo 93 ° C; ri% = 1.4132). The free methylmalondialdehyde is obtained in aqueous solution by acid hydrolysis; it is etherified by azeotropic distillation with benzene and ethyl alcohol in the presence of p-toluenesulfonic acid as a catalyst. The formed l-ethoxy-2-methylpropen- (l) -AL- (3) (boiling point 78 to 80 ⁰ C <= 1.4755) is condensed with an alkali or alkaline earth metal compound of acetylene in liquid ammonia. After the addition of ammonium chloride, the l-ethoxy-2-methyl-3-hydroxypentene- (l) -in- (4) is formed, which is then treated with ethyl orthoformate and a mixture of p-toluenesulfonic acid and phosphoric acid, whereby the desired! , l-diethoxy-2-methylpentene- (2) -in- (4). Boiling point bp _{0; 1} 45 to 46 ° C; ng = 1.4520 to 1.4540; UV absorption maximum at 225 πιμ (in alcohol). Suitable starting materials are compounds in which the 1,1-DiaJkoxy radicals are lower aliphatic radicals, such as ethoxy or isopropoxy groups.

If the C _e acetal - as described below - is first _{condensed with the /? - C 19} aldehyde, one can also start from cyclic acetals. The 1,1-ethylenedioxy-2-methylpentene- (2) -in- (4) is obtained, for. B. by. Cooking the above-described l-ethoxy-2-methyl-3-hydroxypentene- (l) -in- (4) with ethylene glycol in the presence of p-toluenesulfonic acid and distilling the reaction mixture, which has been worked up in the usual way.

The inventive condensation of the /? _{-C 19} -aldehyde takes place with an organometallic derivative of the process for the preparation
of 6,7-dehydro-ß-apo-3-carotenal

Applicant:

F. Hoffmann-La Roche & Co.

Corporation,

Basel, Switzerland)

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

Claimed priority:
Switzerland from February 14, 1958

Dr. Herbert Lindlar, Reinach,

Dr. Marc Montavon, Basel (Switzerland),

Dr. Gabriel Saucy, Nutley, N.J. (V. St. A.),

and Dr. Sidney Frank Schaeren, Bottmingen (Switzerland),

have been named as inventors

C ₆ acetals or an acetal of 3-alkoxy-4-methyl-

hepten- (4) -in- (6) -al- (l) ( _{hereinafter referred to as C 8} ether acetal) in the presence of an inert solvent such as benzene or ether. The / 7-C ₁₉ -aldehyde is preferably condensed with a Grignard or lithium compound of the acetals mentioned, which are used for the condensation before the reaction in the same vessel and in the same solvent. B. from magnesium, ethyl bromide and the corresponding acetal, can produce.

According to one embodiment, the condensation product is best without further purification in Usually hydrolyzed, for example by pouring into a mixture of ice and dilute ammonium chloride solution, the acetylene compound formed being obtained in the form of a viscous oil. These Acetylene compound is subjected to an acid treatment, with elimination of water and alcohol Aldehyde is formed. This reaction is conveniently carried out in an inert solvent such as acetone, alcohol or Ether, in the presence of an aqueous or anhydrous acid such as acetic acid, p-toluenesulfonic acid or hydrochloric acid, carried out. The formation of the aldehyde is particularly easy if one - after another Embodiment ■ - an acid on the organometallic condensation product without previous hydrolysis,

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3 4

like glacial acetic acid, lets act directly. This direct circulating condensation product. UV absorption regulation is appropriate in a solvent, such as mum at 281 πιμ (in petroleum ether).

Acetone or benzene, at temperatures around 0 ° C. The condensation product obtained is in 200 ml

guided. Ether loosened and after. Adding 20 ml of alcoholic

To undertake the condensation with a vinyl hydrochloric acid overnight at room temperature stand ether, z. B. dem-vinyl ethyl ether, one works expediently. The resulting solution is first treated with sodium in the presence of an inert solvent such as bicarbonate solution and then with water, benzene, ether or petroleum ether. As a condensation agent, wash, dry with sodium sulphate and use acidic catalysts, such as zinc chloride evaporated at 45 ° C. in vacuo. About 29 g of a boron trinuoride etherate are obtained. The ether acetals obtained are in the form of viscous, strongly yellow-colored oil. Like the condensation products of 150 ml petroleum ether (boiling range 30 to 45 ° C), this is dissolved in _{an- / 3-C 19} aldehyde and subjected to the acid treatment. vaccinated and left to stand at -10 ⁰ C for a few hours. This is particularly advantageous by heating to The precipitated crystal magma is filtered off with suction and washed 100 ⁰ C with a mixture of sodium acetate in wäß- several times with cold petroleum ether. Made of glacial acetic acid. 15 net in vacuo at 3O ⁰ C and receives 17 g of 4,5-Dehydro-

According to a preferred embodiment of the invention / J-apo-4-carotinal as an ocher-colored powder. Melting point

The just described reaction steps 82 to 83 ° C; UV absorption maximum at 400 ταμ (in

carried out as follows: The G ₆ acetal is by means of a petroleum ether).

organometallic reaction with (SC ₁₉ -aldehyde konden- 18 g of 4,5-dehydro-ß-apo-4-carotinal are in 17 ml

siert and treated the condensation product with acid, suspended 20 ethyl orthoformate, with a Lö-

whereby dehydro-j8-apo-4-carotinal is formed. This solution of 0.24 ml of phosphoric acid and a trace of p-toluene

is acetalized and then mixed with a vinyl ether sulfonic acid in 8 ml of absolute alcohol and some

condensed. The condensation is stirred for hours at room temperature by means of an acid treatment. When everything is resolved

sation product converted into dehydro - /? - apo-3-carotinal. the mixture is left to stand for a further 15 hours

In this embodiment of the method, 1.5 ml of pyridine and then 50 ml of 5pro-

a cyclic acetal used as the starting compound and extracted the centige sodium bicarbonate solution

be, with the organometallic condensation with solution with petroleum ether. The extract is washed with it

the lithium derivative in liquid ammonia, water, dry it with sodium sulfate and steam it

will lead. Before the condensation with the vinyl ether in a vacuum. The residue is in a high vacuum

the aldehyde 30 obtained after the acid treatment is dried at 60 ° C., and 21.7 g of 13- [2,6,6-tri-

acetalized again, which expediently by reacting methylcyclohexen- (l) -yl] -2,7,1 l-trimethyl-1,1-diethoxy

with a mixture of alcohol and orthoformic acid tridecapentaen- (2,6,8,10,12) -in- (4) as a yellow oil. UV-off

ester in the presence of an acidic catalyst, such as phosphorus sorption maxima at 366 and 380 ΐημ (in petroleum ether).

phosphoric acid or p-toluenesulfonic acid, happens. This is with 4 ml of 10 percent zinc chloride solution in

According to another preferred embodiment 35 ethyl acetate and then dropwise with 4.27 g

the C ₆ acetal is added in the presence of an acidic condensate vinyl ether with stirring at 30 to 35 ° C. Man

reacted with vinyl ether. This allows the reaction mixture to stand for 15 hours, gives to

_{The C 8} ether acetal formed in the reaction is converted into a raw

organometallic reaction with / JC ₁₉ -aldehyde condens- 4,9,13-trimethyl-1,3-triethoxypentadecapentaen- (4,8,

and then by acid treatment in De- φο 10,12,14) -in- (6) a solution of 5 g of sodium acetate in

hydro-j8-apo-3-carotinal transferred. 50 ml of 95 percent acetic acid and heat the appliance

The carotenoid obtained in the invention, 6,7-de- mixed under vigorous stirring in nitrogen atmosphere hydro - /> - apo-carotenal-3, provides a valuable dye for 4 hours at 95 to 100 ⁰ C, the Essigdar formed. It can be slowly distilled off as a food coloring or as a poultry ester. The reaction feed additive is allowed to be used for egg yolk coloring. 45 Cool the mixture while stirring, during which the reaction furthermore it is an intermediate product for the synthesis of an important product crystallizes out. It is filtered off, with water carotenoid pigments. washed and recrystallized from petroleum ether or ethanol example 1. 13 g of 6,7-dehydro - ^ - apo-3-carotenal are obtained as

orange-red platelets. Melting point 122 ° C; UV-off

It is first made with ice cooling from 2.7 g of Magne 50 sorption maximum at 417 to 418 πιμ, (in petroleum ether). shim, 14 g of ethyl bromide and 30 ml of absolute ether one

Solution of ethyl magnesium bromide. Example 2 drips in addition
within 30 minutes with vigorous stirring

without cooling, a solution of 16.8 g of 1,1-diethoxy- .. To a solution prepared on the basis of 8 g of lithium

2-methylpentene- (2) -in- (4) in 30 ml of absolute benzene, with lithium amide dripping in 2000 ml of liquid ammonia

when the reaction solution always boils slightly. The Grignard man within one hour 168 g of l, l-diethoxy-2-methyl-

Compound is partly granular, partly in penten- (2) -in- (4) and rinses with 20 ml of ether. Man

viscous form. The mixture is cooked for another 4 to 5 hours and then

30 minutes on the reflux condenser and then a solution of 220 g / 3-C ₁₉ -aldehyde in drops within half an hour

of 30 minutes while cooling with water, a solution of 60 750 ml of absolute ether is added. The reaction mixture is

of 22 g of jö-C ₁₉ aldehyde in 50 ml of absolute ether, stirring continued overnight and then as in the case of

except for a few undissolved fractions, a clear yellow game 1 using 100 g of ammonium chloride

Solution emerges. The mixture is stirred, hydrolyzed and worked up for a further 3 hours. The thereby obtained

continue at room temperature and then pour the reac-4,5-dehydro- _j S-apo-4-carotinal can finally as in

tion solution to a mixture of 20 g ammonium 65 Example 1 are further processed,
chloride and ice. After extraction with ether, washing

with water, drying over sodium sulfate and one example 3
evaporating in vacuo at 45 ° C gives 39 g of 13- [2,6,6-

Trimethylcyclohexen- (l) -yl} -2,7, ll-trimethyl-l, l-di-. 33.6g l, l-diethoxy-2-methylpentene- (2) -in- (4)

ethoxy-6-hydroxytrtdecatetraen- (2,7,9, ll) -in- (4) as viscous 70 diluted with 35 ml of absolute benzene and within

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5 6

one hour at the same time with 15 ml of 10 percent zinc-benzene added, the mixture 3_0 _; Minutes boiled under re-chloride-ethyl acetate solution and a mixture flow, added within the next 30 minutes 100 ml of 17 g of vinyl ether in 17 ml of absolute benzene, allowed to run in water and the mixture again with the temperature by moderate cooling between 1 hour below Refluxed. The reaction mixture is kept at 28 and 30 ° C. The mixture is left over ^; 5 is poured onto 1500 ml of ice water, and the benzene night stand at room temperature, 3 ml of pyridine is added to the phase, 750 ml of saturated sodium chloride solution is poured out and the reaction solution is poured onto a mixture of shakes, dried with about 50 g of potassium carbonate and sodium bicarbonate and ice . After extraction with petroleum, the solvent is evaporated. 94.5 g of ether are obtained, washing with sodium bicarbonate solution and 4,5-dehydro - ^ - apo-4-carotinal as a crystalline product. Drying over potash-sodium sulfate and uni UV absorption maximum at 400 ηαμ; E ₁ ^ = 1730. Steam in a water jet vacuum gives 49 g of crude The conversion to o ^ -Dehydro-jS-apo-S-carotinal takes place 1,3-triethoxy-4-methyl-hepten- (4) -in- (6). The high vacuum distillation (under nitrogen) according to the information in Example 1. gives about 30 g of Beisr> iel5

of a pure product. Boiling point Kp _0i02 63-64 ° C.;

n ² g = 1.4564; UV absorption maximum at 225 πιμ (in 15 to an alcohol prepared starting from 4.5 g of lithium). Solution of lithium amide in 500 ml of liquid ammonia

First, while cooling with ice, 2.7 g of magnet are added dropwise to 69 g of 1,1-ethylenedioxysium, 14 g of ethyl bromide and 30 ml of absolute ether, a 2-methylpentene- (2) -in- (4). After stirring for 5 hours, a solution of ethylmagnesium bromide is produced. _{110 g of j3-C 19} -aldehyde are added dropwise to this over the course of 2 hours, while stirring without cooling in 1000 ml of ether. The mixture is, overnight a solution of 24 g!,!, S-triethoxy ^ -methyl- further stirred and by adding 50 g of ammonium heptene- (4) -in- (6) in 30 ml of absolute ether, the chloride hydrolyzed. Which always boils slightly after the ammo reaction solution has evaporated. Subsequently, suction filtration cooking niaks the reaction solution, washing derman the mixture refluxed for 30 minutes and dropwise same with water, drying over sodium sulfate and within 30 minutes under cooling with water, a 25 evaporation at 4O ⁰ C under vacuum obtained oily rear solution of 25 g jS -C ₁₉ aldehyde in 25 ml of absolute ether was dissolved in 1950 ml of methylene chloride and added to. The mixture is stirred for 3 hours at room -40 ⁰ C first with 78 ml of glacial acetic acid and then inside temperature and then the reaction solution is poured onto a 20 seconds with 78 ml hydrogen bromide 63prozentiger mixture of 20 g of ammonium chloride and ice. Acid added. 1950, sets ml of ice water are added and stirring extraction with ether, washing with water, drying 30, the mixture is heated with water and bicarbonate solution for 5 hours under nitrogen at 0 to 4 ⁰ C. The organic with sodium sulfate and evaporation in vacuo at 45 ° C phase about 200 ml to obtain a crude extract, dried over sodium sulfate and 4O ⁰ C 15- [2,6,6-Trimethylcyclohexen- (l) -yl] -4,9,13-trimethyl- evaporated in vacuo. The resulting crude product 8-hydroxy-l, l, 3-triethoxypentadecatetraen- (4,9, 11, 13) - is dissolved in 500 ml of petroleum ether and kept at -10 ⁰ C- (6), which is used immediately in the next stage 35 left. The precipitated crystals are stored at -50 ° C. UV absorption maxima at 281 and 292 ΐημ (washed in with petroleum ether and at 40 ⁰ C in a vacuum ge petroleum ether). dries. 91 g of 4,5-dehydro - /? - apo-4-carotenal are obtained

The ether solution obtained is mixed with 20 ml of 8 percent from melting point 81 to 83 ° C; UV absorption maxillary alcoholic Hydrochloric acid and 10 g of sodium sulfate are added at 400 ΐημ. The conversion into 6,7-dehydro- / 3-apo- and left to stand overnight at room temperature. 40 3-carotinal takes place as described in Example 1. Then the reaction solution with water and. .

Sodium bicarbonate solution washed over sodium sulfate example ο

dried and evaporated in vacuo at 45 ° C. Starting from 13 g of magnesium in 90 ml of ether and

A viscous oil is obtained which is treated with a solution of 40 g 40 g triethylamine on the one hand and 70 g ethyl bromide in sodium acetate in 30 ml water and 240 ml glacial acetic acid 45 400 ml absolute benzene on the other hand, a Grignar is set. The mixture is warmed to solution for 4 hours. This is cooled to -7 ° C. Then 95 to 100 ^° C. under a nitrogen atmosphere. The reaction mixture is then poured onto ice, while maintaining the low temperature, and extracted with 120 gl, 1,3-triethoxy-4-methylheptene- (4) -in- (6) (according to ether — petroleum ether Washing of the extract prepared in Example 3). After everything has been added, water and sodium bicarbonate ^{solution are added, the mixture I 1} Z is _{stirred for 2} hours and then sodium sulfate is dried and the solvent in a solution of 108.5 g (SC ₁₉ aldehyde in a water-jet vacuum at -7 ° C 45 ° C removed. The residue 150 ml of benzene was added over about 30 minutes, is dissolved hot in 200 ml of methanol and, after seeding, the reaction mixture is I ¹ Z ₂ hours at 3 ⁰ C continued overnight at O to stand ⁰ C. The by Ab Then, within 30 minutes, a crude dehydro- / 3-apo-3-carotinal 55 solution of 120 ml of absolute glacial acetic acid in 150 ml of abso is added dropwise for further purification from petroleum ether with pure benzene so that the temperature is 15 ^{Recrystallized from 0} ° C. to 10 ° C. 15 g of a pure one not exceeded are obtained. The preparation is refluxed for 15 minutes and has a melting point of 122.5 ° C. and the reaction mixture is still warm

Poured 2000 ml of ice water. The benzene-containing layer

Example 4 ^6o is separated off and dried over sodium sulfate. Of the

obtained after evaporation of the solvent

A solution prepared from 13 g of magnesium and 70 g of ethyl stand with 540 ml of an ethyl magnesium bromide solution made from 1200 ml of glacial acetic acid, 200 g of bromide, in sodium acetate and 150 ml of water, ml of absolute benzene is cooled to -7 ° C and 4 hours at 95 ° C ° C, slowly diluted with 500 ml, very slowly with 84 gl, l-diethoxy-2-methylpentene- (2) -in- (4) 65 boiling petroleum ether and approximately added to 800 ml. After the insistent further stirring at -7 ° C 8O ⁰ C water given. The petroleum ether layer is a solution of 108.5 g ^ -C ₁₉ -aldehyde in 150 ml is allowed to stand for 12 hours at -10 ⁰ C and the benzene is added dropwise and the reaction mixture 1 ¹ Z ₂ hours dark red dehydro- / 3-apo-3- carotenal maintained at 40 ° C getrockbei 0 to 5 ^0C. This is followed within net. Yield 90 g. UV absorption maximum at 417πψ; Minutes a solution of 120 ml of glacial acetic acid in 150 ml of 70 E ₁ * = 1755.

Claims (4)

Patent claims: 1. A process for the preparation of 6,7-dehydro - /? - apo-3-carotinal, characterized in that an acetal of 2-methylpentene- (2) -in- (4) -al- (l) in an known way by means of an organometallic reaction either first condenses with 8- [2,6,6-TrimethylcycIohexen- (l) -yl] -2,6-dimethyloctatrien- (2,4 ₎ 6) -al- (l), the Condensation product, if desired after hydrolysis, treated in the customary manner with acid, then acetalized the aldehyde formed in a manner known per se, the acetal condensed in a manner known per se with a vinyl alkyl ether and treated the ether acetal formed in a manner known per se with acid, or in in a manner known per se first with a vinyl alkyl ether and then in a manner known per se by means of an organometallic reaction with SP.ojö-trimethylcyclohexen- (l) -yl] -2,6-dimethyIoctatrien- (2,4,6) -al- (l) condensed and the condensation product formed, if desired after hydrolysis, treated with acid in the usual way. 2. The method according to claim 1, characterized in that that the acid acts directly on the organometallic condensation product formed leaves. 3. The method according to claim 1, characterized in, that glacial acetic acid is used as the acid. 4. The method according to claim 1 to 3, characterized in that cyclic acetals are used and that the organometallic condensation takes place via the corresponding lithium derivatives. Considered publications:
German Auslegeschrift No. 1 021 360;
Chimia, Vol. 12, 1958, pp. 1 to 17. © 009 509/426 5.60