DE1021361B - Process for the preparation of 4- [2, 6, 6-trimethylcyclohexylidene] -2-methylbutene- (2) -al- (1) - Google Patents

Description

GERMAN

The invention relates to a new process for the preparation of a polyenaldehyde of the vitamin Α or / J-carotene series. The procedure is characterized by that you have a 2,6,6-trimethylcyclohexylidenäthylidentria ^ lphosphine, whose aryl groups can carry alkyl or alkoxy groups, with a 2-oxopropanal (l) acetal condensed in an inert solvent, heated and the acetal obtained in the usual way with Hydrolyzed acid.

Compared to a known procedure for the preparation of 4- (2,6,6-trimethylcyclohexylidene) -2-methylbutene- (2) -as- (l) (cf. Lieb. Ann. d. Chem., Vol. 585, 1954, pp. 126 to 141) the present process has the advantage technically more accessible starting materials. While in the known process 2,6,6-trimethylcyclohexanone- (l) must be condensed with an alkoxyacetylene, becomes the starting material for the present process obtained in a technically simple manner from 2,6,6-trimethylcyclohexanone- (l). As a condensation component required acetals of 2-oxopropanal- (l) can be made in a particularly simple manner Methylglyoxal can be obtained.

The required starting products can be produced as follows, for example:

The dialkyl acetals, such as dietary acetal, can e.g. B. according to the information in Beilstein, first supplementary work, 1928, p. 395. The cyclic ethylene acetal can be obtained by the following process:

1 mole of methylglyoxal and 1.2 moles of ethylene glycol are boiled for a few hours in 3 to 4 times the amount of benzene in the presence of a catalytic amount of p-toluenesulfonic acid while continuously distilling off the water formed. When the reaction has ended, the mixture is cooled, poured into cold sodium bicarbonate solution, and the benzene solution is separated off, dried and concentrated. By distilling the residue, the Methvlglyoxaläthylenacetal is obtained with a boiling point of ₁₀ 102 °; nf = 1.4845.

Production of 2,6,6-Trimethylcyclohexylidenäthylidentriarylphosphin

2,6,6-Trimethylcyclohexanone- (l) is condensed with lithium acetylide, partially on the triple bond hydrogenated and treated with a phosphorus trihalide. The 2,6,6-trimethylcyclohexylidene ethyl halide obtained is condensed in an inert solvent with a triarylphosphine and the 2,6,6-trimethyl formed cyclohexylidene äthyltriarylphosphoniumhalogenid for the purpose of splitting off hydrogen halide in one inert solvent with the calculated amount of phenyl or butyllithium added. That works under warming Phosphonium halide in solution. A deep red or brown colored solution of 2,6,6-trimethylcyclo- Process for the production of

4- [2,6,6-trimethylcyclohexylidene] -

2-methy! Buten- (2) -al- (1)

Applicant:

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

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

Claimed priority:
Switzerland from July 22nd 1SS5

Dr. Otto Isler, Dr. Rudolf Rüegg,

Dr. Marc Montavon, Basel,

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

hexylidenäthylidentriarylphosphins, which are expediently used directly for the condensation.

In the first stage of the process according to the invention, the 2-oxopropanal (l) acetal is with a 2,6, o-trimethylcyclohexylidene ethylidene triarylphosphine compound condensed and the condensation product formed in the second stage with elimination of Triarylphosphine oxide converted into the polyenaldehyde acetal. Both reaction stages are expediently in the carried out in the same reaction vessel and without isolating the intermediate product. One used to implement with advantage equivalent amounts of the starting materials and works in an inert solvent such as ether, Petroleum ether, benzene, dioxane, tetrahydrofuran or methylene chloride. The output connections are z. B. mixed in a stirred kettle at room temperature or elevated temperature, where appropriate the air by an inert gas, e.g. B. nitrogen replaced. Lower aliphatic ones are suitable for condensation Acetals of 2-oxopropanal (l), such as dimethyl, diethyl or dibutyl acetals, or cyclic acetals, such as the ethylene or propylene acetal, and as a 2,6,6-trimethylcyclohexylidene ethylidene triarylphosphine compound 2,6,6-trimethylcyclohexylidenethylidene triphenylphosphine. The condensation takes place with the addition of a Solution of the acetal to a solution of the 2,6,6-trimethyl-

709486/489

cyclohexylidenethylidene triarylphosphine instantaneously and is exothermic. Depending on the choice of solvent and the starting materials, the condensation products formed remain in solution or they fail, with usually one Discoloration or lightening of the reaction mixture takes place. In the preferred embodiment of the condensation the starting acetal is in a benzene solution to form a suspension or a solution of 2,6,6-trimethylcyclohexylidenethylidene triarylphosphine added,

example 1

a) 4- [2,6,6 ~ trimethylcyclohexylidene] -2-methylbutene- (2) -al- (Ϊ) -ethylene acetal

To a deep red suspension of 2,6,6-Trimethylcyclohexylidenäthylidentriphenylphosphin - prepared from 9.8 g 2,6,6-Trimethylcyclohexylidenäthyltriphenylphosphoniumbromid (mp. 217 to 218 °) and 1.84 g Phenyllithium in 80 ecm dry ether - one adds Condensation product precipitates. The condensation products gradually disintegrate with stirring in a nitrogen atmosphere on standing, and a solution of 2.4 g of 2-oxopropanal (l) -ethylene acetal rapidly breaks down into the polyenaldehyde acetals when heated (b.p. _lo 102 °; w | ⁶ = 1.4845) in 10 ecm of dry benzene in triarylphosphine oxide. The decomposition is very successful. A voluminous precipitate forms easily with discoloration of the reaction, preferably by heating the mixture for several hours. The reaction mixture is stirred to 35 ° to 80 °. After the end of the mixture for a further 20 minutes, 120 ecm of dry reaction can be added, the polyenaldehyde acetals can be added with benzene, the ether is distilled off until the temperature of the shaking of the organic phase with water from the ent- reaction mixture has reached 60 °, and stirring is continued stood where triarylphosphine oxide and separate for 6 hours in a nitrogen atmosphere at 60 °. Isolate after concentrating the dried solution. You can cold filter the insoluble off, wash the filtrate by partitioning between solvents, Chromato- 20 with water, dry it with sodium sulphate and evaporate graphy or distillation and clean from adhering the solvent. To be freed from still existing organophosphorus phosphorus compounds. Containing impurities are removed, the largely pure polyenaldehyde acetals obtained in this way are taken up as a coloring residue in a little petroleum ether, filtered through a loose or pale yellow colored oil containing aluminum oxide (according to Brockmann, activity spectrum, characteristic absorption maxima on the degree of capacity in an ultraviolet short column II) and evaporates the petroleum ether. One gets wise. 4- [2,6,6-Trimethylcyclohexylidene] 3.5 g of 4- [2,6,6-Trimethylcyclohexylidene] -2-methylbutene-2-methylbutene- (2) -al- (1) -acetals are obtained in the ultraviolet (2) -al- (1) -ethylene acetal. By vacuum distillation, spectrum an absorption maximum at 248 mμ in Petrolman an almost colorless product can be obtained. _{B.p. 0.102} 100 °; show ether. Ultraviolet absorption maximum at 248 πιμ in petrol

In the final stage of the process, the 30 obtained become ether.

Acid hydrolysed polyenaldehyde acetals, the ent- _b) 4.r _2j 6,6-Trimethylcvcloh _e xvliden] -2-methvl-

speaking polyenaldehydes arise. This is done in "buten -" (21 al (ί)

in a manner known per se, for. B. by stirring the

Polyenaldehyde acetals in the presence of water in a 6 g of 4- [2,6,6-trimethylcyclohexylidene] -2-methylbutene-

Water-miscible solvents at room temperature 35 (2) -al- (l) -äthylenacetal are in 80 ecm ethyl alcohol at or higher temperature with a mineral acid, as in solution, mixed with 14 ecm 3N sulfuric acid and sulfuric acid, or with an organic acid How heated to reflux for 30 minutes. Acetic acid or p-toluenesulfonic acid are then diluted. Advantageously, are the mixture with 200 cc of ice-water, it extracts the Polyenaldehydacetale with 90% acetic acid short with 100 cc of petroleum ether, the petroleum ether solution is washed time at 95 ° is heated or in alcoholic solution at 40 with water and then with 5 ° / _o sodium Natriumbicarbonatverdünnter Sulfuric acid stirred for a few hours. To dissolve, dry it with sodium sulphate and evaporate to avoid the losses due to decomposition, it is recommended to remove solvent. 4 g of 4- [2,6,6-trimethyl to work in an inert atmosphere and antioxidant cyclohexylidene] -2-methylbutene- (2) -al- (l) are obtained, which is added by means of a distilling agent. lation can be cleaned. Bp "_ ₀₂ 85 °; Ultraviolet-

The polyene 45 absorption maximum obtained by the present process at 288 πιμ in petroleum ether. That aldehyde, 4- [2,6,6-trimethylcyclohexylidene] -2-methylbu- phenylsemicarbazone forms metha-

ten- (2) -al- (l), has characteristic absorption maxima in the ultraviolet spectrum. As a result of the cis-trans isomerism There are different spatial forms of this aldehyde on the double bonds.

The process product is a valuable intermediate product for the synthesis of vitamin A and / 3-carotene. For example, 4- [2,6,6-trimethylcyclohexylidene] -2-methylbutene- (2) -al- (l) for example with l-oxy-3-methylpentene

nol colorless prisms with a melting point of 158 to 159 °; Ultraviolet absorption maximum at 314 ΐημ in petroleum ether.

Example 2

a) 4- [2,6,6-Trimethylcyclohexylidene] -2-methylbutene- (2) -al- (l ) diethylacetal

3 g of 1,1 diethoxypropanone (2) are, as in Example 1, with 2,6,6-trimethylcyclohexylidenethylidene triphenyl

(2) -in- (4) are condensed, the condensation product 55 phosphine - from 9.8 g 2,6,6-trimethylcyclohexylidene acetylated in the wrong order and partially hydrogenated on the triple äthyltriphenylphosphoniumbromid and 1.84 g phenyl bond and from the obtained Ester
due to the action of water-releasing agents

lithium produced in 80 ecm ether - condensed and worked up. The 4- [2,6,6-trimethylcyclohexylidene] -2-methylbutene- (2) -al- (1) -diethylacetal is obtained Condensation with vinyl ether, heating with acid, 60 an absorption maximum in the ultraviolet spectrum one obtains o-P.o.ö-TrimethylcyclohexylidenJ - ^ - methyl- at 248 πιμ in petroleum ether. Yield: 3.5 g.

Vitamin A can be obtained. Through the formation of the acetal,

hexadiene- (2,4) -al- (l), which by acetalization, condensation of the acetal formed with a propenyl ether and heating the condensation product with acid in S-ß.o.ö-trimethylcyclohexylideneJ ^ o-dimethyloctatriene-65 (2,4,6) -al- (l) can be converted. This is doubled by condensation with acetylene, subsequent Elimination of water with rearrangement, partial hydrogenation of the triple bond and isomerization into / J-carotene converted.

b) 4-r2,6,6-trimethylcyclohexylidene] -2-methylbutene- (2) -al- (l)

5 g of 4-r2,6,6-trimethylcyclohexylidene] -2-methylbutene- (2) -al- (1) -diethylacetal are dissolved in 90 ecm glacial acetic acid, mixed with 10 ecm water and 10 g sodium acetate and Heated to 95 ° for 2 hours. The mixture is then diluted with 200 ecm of water and extracted with petroleum

70 ether, washes the petroleum ether solution with water and with

5% sodium bicarbonate solution, dry it with sodium sulfate and evaporate the solvent. Distillation in vacuo gives 4- [2,6,6-trimethylcyclohexylidene] -2-methylbutene- (2) -al- (l) with a _{boiling point of} 85 °; Ultraviolet absorption maximum at 288 ΐημ in petroleum ether. Yield: 3 g.

For the preparation of the starting compounds, protection is not given in the context of the present invention desired.

Claims (2)

PATENT CLAIMS: IO 1. Process for the preparation of 4- [2,6,6-trimethylcyclohexylidene] -2-methylbutene- (2) -al- (l), characterized in that a 2,6,6-trimethylcyclohexylidenethylidene triarylphosphine compound, whose Aryl groups can carry alkyl or alkoxy groups, with a 2-oxopropanal (l) acetal in one Inert solvent condensed, the condensation product is preferably heated to 35 to 80 ° and the obtained 4- [2,6,6-trimethylcyclohexylidene] -2-methylbutene- (2) -al- (1) -acetal hydrolyzed in the usual way with acid. 2. The method according to claim 1, characterized in that the starting material is 2,6,6-trimethylcyclohexylidene ethylidene triphenylphosphine and 2-oxopropanal (l) ethylene acetal or 2-oxopropanal (l) diethylacetal used. Considered publications:
Dear. Ann. d. Chem., Vol. 585, 1954, pp. 126-141. © 709 846/489 12.