DE1024510B - Process for the production of carotenoids - Google Patents

Description

GERMAN

The invention relates to a process for the preparation of carotenoids. The process is characterized in that the double-sided condensation of acetylene by an organometallic reaction in a manner known _{per se with a C 19} aldehyde of the general formula

R-CH = C-CH = CH-CH = C-CHO

y y

CH ₃ CH ₃

in which R denotes a hydrocarbon radical with the carbon structure of cyclogeraniol, the organometallic condensation product obtained is _{treated with excess lithium aluminum hydride after the customary hydrolysis to the corresponding C 40} acetylenediol in the presence of an organic tertiary amine.

The C ₄₀ acetylenediols are built up, for. B. after the in Liebigs Ann. d. Chem., Vol. 570, 1950, pp. 54 to 69, and Vol. 594, 1955, pp. 165 to 176. A reaction is also known from J. Chem. Soc, 1954, pp. 4006 to 4009, according to which 1,4-acetylene glycols can be converted into diene compounds by means of lithium aluminum hydride. According to those statements, however, only a yield of 35% is achieved when carried out in an ethereal solution. In the present process, this reaction method is transferred to the significantly more complex C ₄₀ diols. Surprisingly, it was found that only a few undesirable side reactions occur and that this method can also be used for higher, less stable 1,4-acetylenediols. In addition, it has been found that the yield can be increased markedly if the reaction is carried out in a tertiary amine solvent.

_{The C 19} aldehydes required to produce the C ₄₀ acetylenediols can be produced, for example, as follows:

Method of manufacture
of carotenoids

Applicant:

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

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

Claimed priority:
Switzerland from July 20, 1955

Dr. Otto Isler, Dr. Rudolf Rüegg,

Dr. Marc Montavon, Basel,

and Dr. Paul Zeller, Neuallschwil, Basel (Switzerland),
have been named as inventors

8- [2 ', 6', 6 ^/ -trimethylcyclohexen- (2 ') ylidene] -

2,6-dimethyloctatriene- (2,4,6) -al- (l)
[abbreviated: dehydro- (retro) -C ₁₉ -aldehyde]
It is analogous to the / 3-C ₁₉ aldehyde, starting from 4- [2 ', 6', 6'-trimethylcyclohexen- (2 ') -ylidene] -2-methylbutene- (2) -al- (l) [ = Dehydro- (retro) -C ₁₄ -aldehyde], which can be obtained by treating /? - C ₁₄ -aldehyde with N-bromosuccinimide and subsequent heating with quinoline.

octatriene- (2,4,6) -al- (l)
[abbreviated: / JC ₁₉ -aldehyde]

4- [2 ', 6 ^/ , 6'-Trimethylcyclohexen- (l ^/ ) -yl] -2-methylbutene- (2) -al- (l) [= / JC ^ -aldehyde] is with the by condensation of l , l-diethoxypropanone- (2) available with lithium acetylide 2-methyl-2-hydroxybutyne- (3) -al- (l) -diethylacetal condensed by a Grignard reaction, the condensation product formed is heated with excess lithium aluminum hydride, and the obtained 8 - [ 2 ', 6', 6 '- Trimethylcyclohexen - (1') - yl] -2,6 - dimethyloctatrien- (2,4,6) -al- (1) -diethylacetal is hydrolyzed with acid.

2,6-dimethyloctatriene- (2,4,6) -al- (l)
[abbreviated: Dehydro - /? - C ₁₉ -aldehyde]

It is analogous to the / 3-C ^ -aldehyde, starting from 4- [2 ', 6', o'-trimethylcyclohexadien- (1 ', 3') -yl] -2-methylbutene- (2) -al- ( l) [= dehydro- / 3-C ₁₄ -aldehyde), which is obtained by treating the dehydro- (retro) -C ₁₄ -aldehyde with isopropenyl acetate and subsequent mild saponification of the 4- [2 ', 6', 6'- Trimethylcyclohexadien- (l ^/ , 3 ') - yl] -2-methyl-l-acetoxybutadiene- (l, 3) can win.

octatriene- (2,4,6) -al- (l)
[abbreviated: Iso-C ₁₉ -aldehyde]

It is analogous to the /? - C ₁₉ aldehyde, starting from 4- [2 ', 6', 6'-trimethyl-cyclohexylidene] -2-methylbutene- (2) -al- (1) [iso-cyaldehyde ], which can be obtained as follows:

The ethoxyacetylenecarbinol obtained by condensation of ethoxyacetylene with 2,6,6-trimethylcyclohexanone- (l) is in a known manner at the

70.9 880/423

3 4

Triple bond partially hydrogenated and treated with acid hydroxyl group attached, while the second mole with delt. The resulting 2,6,6-Trimethylcyclohexyliden- the acetylene bond reacts and thereby the terminal acetaldehyde is acetalized, the acetal formed is permanent carbon atom condensable, in the presence of an acidic condensing agent with the formed dimagnesium halide compound condenses a propenyl ether, and the condensation is appropriate in the same solvent with the product is treated with acid. C ₁₉ aldehyde. In the condensation of 1 mole of acetylene, the condensation product is hydrolyzed in the usual way, _{ideally without purification, organometallic reaction with 2 moles of the C 19} aldehyde, for example by pouring it into a mixture of ice, acetylenedimagnesium halides can be obtained with dilute sulfuric acid. If one uses for the Grignard reaction with twice the molar amount of the io condensation the same C ₁₉ aldehyde as in the Her-C ₁₉ aldehyde condensation. The acetylenedimagnesium position of Ca-acetylenecarbinol, so the above halides can be formed in a manner known per se by the described symmetrical /? -, bis-dehydro - /? -, iso action of acetylene on a solution of alkyl and bisdehydro (retro) -C ₄₀ acetylenediols. If magnesium halide is condensed in an inert solvent, the C ₂₁ -acetylenecarbinol can be produced with another. For this purpose, an ethereal 15 C ₁₉ aldehyde is expedient, which gives an asymmetric C ₄₀ acetylenic solution of the alkyl magnesium halide in a diol, for example 1- [2 ', 6', 6'-trimethylcyclohexene (1 ') acetylene atmosphere for several hours stirred or geyl] -18- [2 ', 6', 6 ^/ -trimethylcyclohexadien- (r, 3 ') - yl] -3,7,12, shakes. Suitable alkyl magnesium halides are 16-tetramethyl-8, ll-dihydroxyoctadecahexaen- (2,4,6,12, for example ethyl, butyl and hexylmagnesium 14,16) -in- (9) [abbreviated to dehydro-β-Qg- acetylenediol bromide or magnesium chloride. The acetylenedi- 20 named] from / JC ₂₁ -acetylenecarbinol and dehydro - /? - C ₁₉ -magnesium halides are deposited as heavy aldehydes or from dehydro - /? - C ₂₁ -acetylenecarbinol and oils or in solid form. 2 mol of β-, dehydro- / ?-, JS-C ₁₉ -aldehyde are dissolved.

Iso- or dehydro (retro) aldehyde in an inert. The C ₄₀ acetylenediols obtained in this way have solvents such as diethyl ether, the solution gives 2 mol of active hydrogen atoms under Zerewitinoff determination, vigorously stirring the suspension of the acetylenedimagne- 25 and possesses im Ultraviolet spectrum charaktesiumhalogenids and stir the mixture for several hours ristic absorption maxima. They can now be further processed according to the invention precisely as follows at room temperature or at the boiling point. Solvent. _{The C 10} -acetylenediols are treated with excess product by hydrolysis of the condensation to give 1,18-di- [2 ', 6', 6'-trimethylcyclo-lithium aluminum hydride. Partial hydrogenation of hexen- (l ') - yl] - or l, 18-di- [2', 6 ', 6'-trimethylcyclohexa- 30 and cleavage of the hydroxyl groups take place at the same time dien- (1', 3 ') - yl] - or 1.lS-Di-P'.o ^ o'-trimethylcyclo- timely if the C ₁₀ -acetylenediol is in a tertiary hexyüden] - or!, lS-Di- ^ '. o'jö'-trimethylcyclohexene - Amine as solvent with excess lithium (2 ') - ylidenj- or!, IS-S ^. ^. Lo-tetramethyl-S.II-dihyaluminium hydride at room temperature or with increased hydroxyoctadecahexaen (2,4,6 , 12,14,16) -in- (9) - treated in the following temperature. Suitable solvents are the ß- or bisdehydro - /? - or iso- or bisdehydro- 35 tertiary amines, such as Ν, Ν-diethylaniline or N-ethyl- (retro) -C ₄₀ -acetylenediol. morpholine. To avoid losses by oxidation, it is also the ß or dehydro - / -. Or iso or "it is recommended to work in an inert atmosphere dehydroepiandrosterone (retro) -C ₁₉ -aldehydzuerstinflüssigemAmmoniak In the preferred. Embodiment is stirred with an alkali or alkaline earth _{acetylide and C 40} acetylenediol in Ν, Ν-diethylaniline with 2 to 4 mol only then the condensation product formed, preferably 40 lithium aluminum hydride at 50 to 80 ° C in a manner after hydrolysis to the corresponding . acetylene nitrogen atmosphere is obtained from / 5-C ₄₀ -Acetylendiol carbinol, .beta. with 1 mole, dehydro - / -, iso- or dehydro the 7,7'-dihydro - /? - carotene, from the Bisdehydro - /? - C ₄₀ - (retro) -C ₁₉ -aldehyde convert the S ^ .S ^ '- bisdehydro ^ J'-dihydro-jS-tion by means of an organometallic reac- acetylenediol. The condensation of the C ₁₉ -aldehyde with carotene , from the iso-C ₄₀ -ketylenediol the 5,5'-dihydrode metal acetylide in liquid ammonia can be 45 ß-carotene and from the bisdehydro - (retro) -C ₄₀ -acetylene under increased pressure at room temperature or under dioldas4,4 ^/ -dehydro - /? - carotene. Asymmetric carotenoid compounds are formed from the asymmetric normal pressure at the boiling point of ammonia, C _{40 diols.} The 3,4-cation LithiumacetyHd is preferably used for condensation, for example from dehydro-β-C _{40 -diol.} The C ₁₉ aldehyde can be converted into a dehydro-7,7'-dihydro- / 3-carotene.

inert solvents such as diethyl ether are added. 50 The carotenoids obtained can be

The condensation product can be produced by adding a sation, partitioning between solvents and chromium

Purify ammonium salt before removing ammonia or matography. They show in the ultraviolet

characteristic absorption maxima by adding acid after removal of the ammonia spectrum. she

be hydrolyzed. This can be obtained by adding antioxidants that too

lO-P'jo'.o'-Trimethylcyclohexen-il ^ -ylj- or 10-P'jo'.ö'- 55 be present during the course of the synthesis

Trimethylcyclohexadien- (1 ', 3') - yl] - or 10- [2 ', 6', 6'-Tn- can be stabilized. The process products

methylcyclohexylidene] - or 10- [2 ', 6', 6'-TrimethyIcyclo- are valuable dyes for coloring food

hexen- (2 ') - ylidene] -4,8-dimethyldecatriene- (4,6,8) -in- (1) -ol- (3).

[abbreviated ß-, dehydro - /? -, iso- or dehydro- (retro) -C ₂₁ - example 1

called acetylene carbinol]. The C ₂₁ acetylene carbinoles are 60 __, _.,

thick oils. When determining the Zerewitinoff, they show 7,7 -Dihydro - ^ - carotm

1 mol in the cold and 2 mol active in the heat. One suspends 5.6 parts by weight of 1,18-di- [2 ', 6', 6'-

Hydrogen atoms and in the ultraviolet spectrum charak- trimethylcyclohexen-il ^ -ylj-S ^. ^. Lo-tetramethyl-S.li-

statistical absorption maxima. The C _2x -acetylene-dihydroxyoctadecahexaen- (2,4,6,12,14,16) -in- (9) in 140

carbinols are then replaced by an organometallic 65 volume parts Ν, Ν-diethylaniline, which adds to the suspension a

Reaction with a second mol of ß-, dehydro - /? -, iso solution of 1.2 parts by weight of lithium aluminum hydride

or dehydro- (retro) -C ₁₉ -aldehyde condensed. The before- in 30 parts of volume with absolute ether with stirring

The preferred embodiment consists in gradually increasing to 10 to 15 ° C. and heating the mixture

the C ₂₁ acetylene carbinol 2 moles of alkyl magnesium halide for 3 hours at 60 ° C in a nitrogen atmosphere. the

lets act in ether. The first mole of the 70 reaction mixture is then added to a mixture of

Poured 250 parts by volume of 3 η-sulfuric acid and 200 parts by weight of ice and extracted with ether. The ether solution is washed successively with ice-cold 3 N sulfuric acid, water and 5 ° / _o sodium bicarbonate solution, dried and evaporated with sodium sulphate. The residue is purified by crystallization from methylene chloride-methanol. In this way, 5 ^{parts by weight of 7,7 /} -dihydro- / 3-carotene are obtained as orange crystals. M.p. 183 to 184 ° C; UV absorption maxima at 382.5, 404 and 429 ΐημ in petroleum ether.

Example 2
7,7'-dihydro - /? - carotene

5.6 parts by weight of 1,18-di- [2 ', 6', 6'-trimethylcyclohexen- (l ') -yl] -3,7,12,16-tetramethyl-8,11-dihydroxyoctadecahexaen- (2 , 4,6,12,14,16) -in- (9) in 100 parts by volume of N-ethylmorpholine, gradually adds a solution of 1.3 parts by weight of lithium aluminum hydride in 30 parts by volume of absolute ether to the solution while stirring at 10 to 15 ° C , the reaction solution is heated at 45 ° C. for 5 hours and the reaction mixture is worked up in the manner indicated in Example 1. The 7.7 ^/ dihydro- /? -Carotene with a melting point of 183 to 184 ° C. is obtained. Yield 4.5 parts by weight.

Example 3

4,4'-dehydro- / 3-carotene

By treating 16 parts by weight of 1,18-di- [2 ^/ , 6 ^/ , 6 ^/ -trimethylcyclohexen- (2 ') - ylidene] -3,7,12,16-tetramethyl-8,11-dihydroxyoctadecahexaen- (2, 4,6,12,14,16) -in- (9) with lithium aluminum hydride and working up the reaction product in the manner described in Example 1, the 4,4 ^/ -dehydro- /? - carotene is obtained in the form of purple crystals from methylene chloride. Methanol; M.p. 191 to 193 ° C; UV absorption maxima at 446, 472 and 503 ηιμ (in petroleum ether).

Example 4
S ^ -Dehydro- ^ '- dihydro-ß-carotene

By treating 6.2 parts by weight of l- \ 2 ', &, & - trimethylcyclohexen- (10-yl] -18- [2 ^ 6 ^ 6 ^ rimethylcyclohexadiene- (1 ^ 3> yl] -3,7,12, 16-tetramethyl-8, ll-dihydroxyoctadecahexaen- (2,4,6,12,14,16) -in- (9) with lithium aluminum hydride and working up the reaction product in the manner described in Example 1 gives 3.5 parts by weight of 3, 4-dehydro-7,7 ^/ 5 -dihydro- _J-carotene as an orange-colored crystals from methylene chloride-methanol, mp 179 ° C;. UV absorption maxima at 384, 405 and πιμ in petroleum ether.

Claims (2)

PATENT CLAIM: 1. Process for the preparation of carotenoids, characterized in that the two-sided condensation of acetylene with the aid of an organometallic reaction with a C ₁₉ aldehyde of the general formula R-CH = C-CH = CH-CH = C-CHO
CH ₃ CH ₃ in which R denotes a hydrocarbon radical with the carbon structure of cyclogeraniol, the organometallic condensation products obtained and the C ₄₀ diols obtained therefrom after the customary hydrolysis are treated with excess lithium aluminum hydride in a tertiary amine as solvent, preferably at 50 to 80.degree. 2. The method according to claim 1, characterized in that 1 mol of the C ₄₀ diol formed in diethylaniline is heated to 60 ° C with 2 to 4 mol of lithium aluminum hydride. Considered publications:
Swiss Patent No. 299106;
Liebigs Ann. d. Chem., Vol. 570, 1950, pp. 54 to 72; Vol. 588, 1954, pp. 117ff .; Vol. 594, 1955, pp. 165 to 176; J. Am. Chem. Soc, Vol. 77, 1955, p. 1053;
J. Chem. Soc, 1954, 4006-4009. A priority document was displayed when the registration was announced. © 709 880/423 2.58